Pulmonary vascular disease in Veterans with post-deployment respiratory syndrome.

Exertional dyspnea has been documented in US military personnel after deployment to Iraq and Afghanistan. We studied whether continued exertional dyspnea in this patient population is associated with pulmonary vascular disease (PVD). We performed detailed histomorphometry of pulmonary vasculature in 52 Veterans with biopsy-proven post-deployment respiratory syndrome (PDRS) and then recruited five of these same Veterans with continued exertional dyspnea to undergo a follow-up clinical evaluation, including symptom questionnaire, pulmonary function testing, surface echocardiography, and right heart catheterization (RHC). Morphometric evaluation of pulmonary arteries showed significantly increased intima and media thicknesses, along with collagen deposition (fibrosis), in Veterans with PDRS compared to non-diseased (ND) controls. In addition, pulmonary veins in PDRS showed increased intima and adventitia thicknesses with prominent collagen deposition compared to controls. Of the five Veterans involved in our clinical follow-up study, three had borderline or overt right ventricle (RV) enlargement by echocardiography and evidence of pulmonary hypertension (PH) on RHC. Together, our studies suggest that PVD with predominant venular fibrosis is common in PDRS and development of PH may explain exertional dyspnea and exercise limitation in some Veterans with PDRS.

Physical Activity and Incident Obesity Across the Spectrum of Genetic Risk for Obesity.

Importance: Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic variability, increasing risk of obesity. Objective: To use activity, clinical, and genetic data from the All of Us Research Program (AoURP) to explore the association of genetic risk of higher body mass index (BMI) with the level of physical activity needed to reduce incident obesity. Design, Setting, and Participants: In this US population-based retrospective cohort study, participants were enrolled in the AoURP between May 1, 2018, and July 1, 2022. Enrollees in the AoURP who were of European ancestry, owned a personal activity tracking device, and did not have obesity up to 6 months into activity tracking were included in the analysis. Exposure: Physical activity expressed as daily step counts and a polygenic risk score (PRS) for BMI, calculated as weight in kilograms divided by height in meters squared. Main Outcome and Measures: Incident obesity (BMI ≥30). Results: A total of 3124 participants met inclusion criteria. Among 3051 participants with available data, 2216 (73%) were women, and the median age was 52.7 (IQR, 36.4-62.8) years. The total cohort of 3124 participants walked a median of 8326 (IQR, 6499-10 389) steps/d over a median of 5.4 (IQR, 3.4-7.0) years of personal activity tracking. The incidence of obesity over the study period increased from 13% (101 of 781) to 43% (335 of 781) in the lowest and highest PRS quartiles, respectively (P = 1.0 × 10-20). The BMI PRS demonstrated an 81% increase in obesity risk (P = 3.57 × 10-20) while mean step count demonstrated a 43% reduction (P = 5.30 × 10-12) when comparing the 75th and 25th percentiles, respectively. Individuals with a PRS in the 75th percentile would need to walk a mean of 2280 (95% CI, 1680-3310) more steps per day (11 020 total) than those at the 50th percentile to have a comparable risk of obesity. To have a comparable risk of obesity to individuals at the 25th percentile of PRS, those at the 75th percentile with a baseline BMI of 22 would need to walk an additional 3460 steps/d; with a baseline BMI of 24, an additional 4430 steps/d; with a baseline BMI of 26, an additional 5380 steps/d; and with a baseline BMI of 28, an additional 6350 steps/d. Conclusions and Relevance: In this cohort study, the association between daily step count and obesity risk across genetic background and baseline BMI were quantified. Population-based recommendations may underestimate physical activity needed to prevent obesity among those at high genetic risk.

Genetics of Pulmonary Pressure and Right Ventricle Stress Identify Diabetes as a Causal Risk Factor.

Background Epidemiologic studies have identified risk factors associated with pulmonary hypertension and right heart failure, but causative drivers of pulmonary hypertension and right heart adaptation are not well known. We sought to leverage unbiased genetic approaches to determine clinical conditions that share genetic architecture with pulmonary pressure and right ventricular dysfunction. Methods and Results We leveraged Vanderbilt University's deidentified electronic health records and DNA biobank to identify 14 861 subjects of European ancestry who underwent at least 1 echocardiogram with available estimates of pulmonary pressure and right ventricular function. Analyses of the study were performed between 2020 and 2022. The final analytical sample included 14 861 participants (mean [SD] age, 63 [15] years and mean [SD] body mass index, 29 [7] kg/m2). An unbiased phenome-wide association study identified diabetes as the most statistically significant clinical International Classifications of Diseases, Ninth Revision (ICD-9) code associated with polygenic risk for increased pulmonary pressure. We validated this finding further by finding significant associations between genetic risk for diabetes and a related condition, obesity, with pulmonary pressure estimate. We then used 2-sample univariable Mendelian randomization and multivariable Mendelian randomization to show that diabetes, but not obesity, was independently associated with genetic risk for increased pulmonary pressure and decreased right ventricle load stress. Conclusions Our findings show that genetic risk for diabetes is the only significant independent causative driver of genetic risk for increased pulmonary pressure and decreased right ventricle load stress. These findings suggest that therapies targeting genetic risk for diabetes may also potentially be beneficial in treating pulmonary hypertension and right heart dysfunction.

Cardiometabolic Risk Factors Associated With Right Ventricular Function and Compensation in Patients Referred for Echocardiography.

Background Pulmonary hypertension and right ventricular (RV) dysfunction are drivers of adverse outcomes; however, modifiable risk factors for RV dysfunction are not well described. We investigated the association between clinical markers of metabolic syndrome and echocardiographic RV function in a large referral population. Methods and Results Using electronic health record data, we performed a retrospective cohort study of patients aged ≥18 years referred for transthoracic echocardiography between 2010 and 2020 with RV systolic pressure (RVSP) or tricuspid annular plane systolic excursion (TAPSE) values. Pulmonary hypertension was defined by RVSP >33 mm Hg and RV dysfunction by TAPSE ≤1.8 cm. Our sample included 37 203 patients of whom 19 495 (52%) were women, 29 752 (83%) were White, with a median age of 63 years (interquartile range, 51-73). Median (interquartile range) RVSP was 30.0 mm Hg (24.0-38.7), and median TAPSE was 2.1 cm (1.7-2.4). Within our sample, 40% had recorded RVSP >33 mm Hg, and 32% with TAPSE <1.8 cm. Increase in RVSP from normal (<33 mm Hg) to mildly elevated (33-39 mm Hg) or elevated (>39 mm Hg) was associated with lower low-density lipoprotein and high-density lipoprotein, and higher hemoglobin A1c and body mass index (P<0.001). A decrease in TAPSE between groups of TAPSE >1.8 cm, TAPSE 1.5-1.8 cm, and TAPSE <1.5 cm was associated with increased triglyceride:high-density lipoprotein ratio and hemoglobin A1c, and decreased body mass index, low-density lipoprotein, high-density lipoprotein, and systolic blood pressure (P<0.001). Most associations between cardiometabolic predictors and RVSP and TAPSE were nonlinear with clear inflection points associated with higher pulmonary pressure and lower RV function. Conclusions Clinical measures of cardiometabolic function were highly associated with echocardiographic measures of right ventricular function and pressure.

Physical Activity Over the Lifecourse and Cardiovascular Disease.

Despite improvements in cardiovascular care in recent decades, cardiovascular disease (CVD) remains a leading cause of death worldwide. At its core, CVD is a largely preventable disease with diligent risk factor management and early detection. As highlighted in the American Heart Association's Life's Essential 8, physical activity plays a central role in CVD prevention at an individual and population level. Despite pervasive knowledge of the numerous cardiovascular and noncardiovascular health benefits of physical activity, physical activity has steadily decreased over time and unfavorable changes in physical activity occur throughout people's lives. Here, we use a lifecourse framework to examine the evidence reporting on the association of physical activity with CVD. From in utero to older adults, we review and discuss the evidence detailing how physical activity may prevent incident CVD and mitigate CVD-related morbidity and death across all life stages.

Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis.

Rationale: Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives: We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods: We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006-September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998-December 20, 2013). Measurements and Main Results: From an N of 4,737 complete case patients with mPAP of 19-24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9-61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ⩾19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7-73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570-1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ⩾3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ⩾3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2-69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671-3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55-0.62; P < 0.001) and 49% (95% confidence interval, 0.38-0.69; P < 0.001) improvements in survival were observed for PAC ⩾3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions: These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ⩾3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.

Clinical features do not identify risk of progression from isolated postcapillary pulmonary hypertension to combined pre- and postcapillary pulmonary hypertension.

Pulmonary hypertension is a common sequelae of left heart failure and may present as isolated postcapillary pulmonary hypertension (Ipc-PH) or combined pre- and postcapillary pulmonary hypertension (Cpc-PH). Clinical features associated with progression from Ipc-PH to Cpc-PH have not yet been described. We extracted clinical data from patients who underwent right heart catheterizations (RHC) on two separate occasions. Ipc-PH was defined as mean pulmonary pressure >20 mmHg, pulmonary capillary wedge pressure >15 mmHg, and pulmonary vascular resistance (PVR) < 3 WU. Progression to Cpc-PH required an increase in PVR to ≥3 WU. We performed a retrospective cohort study with repeated assessments comparing subjects that progressed to Cpc-PH to subjects that remained with Ipc-PH. Of 153 patients with Ipc-PH at baseline who underwent a repeat RHC after a median of 0.7 years (IQR 0.2, 2.1), 33% (50/153) had developed Cpc-PH. In univariate analysis comparing the two groups at baseline, body mass index (BMI) and right atrial pressure were lower, while the prevalence of moderate or worse mitral regurgitation (MR) was higher among those who progressed. In age- and sex-adjusted multivariable analysis, only BMI (OR 0.94, 95% CI 0.90-0.99, p = 0.017, C = 0.655) and moderate or worse MR (OR 3.00, 95% CI 1.37-6.60, p = 0.006, C = 0.654) predicted progression, but with poor discriminatory power. This study suggests that clinical features alone cannot distinguish patients at risk for development of Cpc-PH and support the need for molecular and genetic studies to identify biomarkers of progression.

Daily Step Counts Before and After the COVID-19 Pandemic Among All of Us Research Participants.

This cohort study of US adults examines changes in physical activity following the onset of the COVID-19 pandemic.

Feasibility of joint mapping of triglyceride saturation and water longitudinal relaxation in a single breath hold applied to high fat-fraction adipose depots in the periclavicular anatomy.

INTRODUCTION: Simultaneous mapping of triglyceride (TAG) saturation and tissue water relaxation may improve the characterization of the structure and function of anatomies with significant adipose tissue. While several groups have demonstrated in vivo TAG saturation imaging using MRI, joint mapping of relaxation and TAG saturation is understudied. Such mappings may avoid bias from physiological motion, if they can be done within a single breath-hold, and also account for static and applied magnetic field heterogeneity. METHODS: We propose a transient-state/MR fingerprinting single breath-hold sequence at 3 T, a low-rank reconstruction, and a parameter estimation pipeline that jointly estimates the number of double bonds (NDB), number of methylene interrupted double bonds (NMIDB), and tissue water T1, while accounting for non-ideal radiofrequency transmit scaling and off-resonance effects. We test the proposed method in simulations, in phantom against MR spectroscopy (MRS), and in vivo regions in and around high fat fraction (FF) periclavicular adipose tissue. Partial volume and multi-peak transverse relaxation effects are explored. RESULTS: The simulation results demonstrate accurate NDB, NMIDB, and water T1 estimates across a range of NDB, NMIDB, and T1 values. In phantoms, the proposed method's estimates of NDB and NMIDB correlate with those from MR spectroscopy (Pearson correlation ≥0.98), while the water T1 estimates are concordant with a standard phantom. The NDB and NMIDB are sensitive to partial volumes of water, showing increasing bias at FF < 40%. This bias is found to be due to noise and transverse relaxation effects. The in vivo periclavicular adipose tissue has high FF (>90%). The adipose tissue NDB and NMIDB, and muscle T1 estimates are comparable to those reported in the literature. CONCLUSION: Robust estimation of NDB, NMIDB at high FF and water T1 across a broad range of FFs are feasible using the proposed methods. Further reduction of noise and model bias are needed to employ the proposed technique in low FF anatomies and pathologies.

Transpulmonary generation of cell-free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms.

Circulating cell-free hemoglobin (CFH) is elevated in pulmonary arterial hypertension (PAH) and associated with poor outcomes but the mechanisms are unknown. We hypothesized that CFH is generated from the pulmonary circulation and inadequately cleared in PAH. Transpulmonary CFH (difference between wedge and pulmonary artery positions) and lung hemoglobin α were analyzed in patients with PAH and healthy controls. Haptoglobin genotype and plasma hemoglobin processing proteins were analyzed in patients with PAH, unaffected bone morphogenetic protein receptor type II mutation carriers (UMCs), and control subjects. Transpulmonary CFH was increased in patients with PAH (p = 0.04) and correlated with pulmonary vascular resistanc (PVR) (r s = 0.75, p = 0.02) and mean pulmonary arterial pressure (mPAP) (r s = 0.78, p = 0.02). Pulmonary vascular hemoglobin α protein was increased in patients with PAH (p = 0.006), especially in occluded vessels (p = 0.04). Haptoglobin genotype did not differ between groups. Plasma haptoglobin was higher in UMCs compared with both control subjects (p = 0.03) and patients with HPAH (p < 0.0001); patients with IPAH had higher circulating haptoglobin levels than patients with HPAH (p = 0.006). Notably, circulating CFH to haptoglobin ratio was elevated in patients with HPAH compared to control subjects (p = 0.02) and UMCs (p = 0.006). Moreover, in patients with PAH, CFH: haptoglobin correlated with PVR (r s = 0.37, p = 0.0004) and mPAP (r s = 0.25, p = 0.02). Broad alterations in other plasma hemoglobin processing proteins (hemopexin, heme oxygenase-1, and sCD163) were observed. In conclusion, pulmonary vascular CFH is associated with increased PVR and mPAP in PAH and dysregulated CFH clearance may contribute to PAH pathology. Further study is needed to determine whether targeting CFH is a viable therapeutic for pulmonary vascular dysfunction in PAH.

Ferroptosis Promotes Pulmonary Hypertension.

Background: Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species (ROS) generation, results in lipid peroxidation-induced ferroptosis. Ferroptosis is an inflammatory mode of cell death as it both promotes complement activation and recruits macrophages. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit disrupted lipid metabolism and increased ROS production, and there is ectopic complement deposition and inflammatory macrophage accrual in the surrounding vasculature. However, the integrative effects of ferroptosis on metabolism, cellular landscape changes in the lung, complement induction, and pulmonary vascular remodeling are unknown. Methods: Multi-omics analyses in rodents and a genetic association study in humans evaluated the role of ferroptosis in PAH. Results: Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity and improved right ventricular function in monocrotaline rats. RNA-seq and proteomics analyses demonstrated ferroptosis was induced with increasingly severe PAH. Metabolomics and proteomics data showed ferroptosis inhibition restructured lung metabolism and altered phosphatidylcholine and phosphatidylethanolamine levels. RNA-seq, proteomics, and confocal microscopy revealed complement activation and pro-inflammatory cytokines/chemokines were suppressed by ferrostatin-1. Additionally, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundances and gene activation patterns in the lungs as revealed by deconvolution RNA-seq. Finally, the presence of six single-nucleotide polymorphisms in ferroptosis genes were independently associated with pulmonary hypertension severity in the Vanderbilt BioVU repository. Conclusions: Rodent and human data nominate ferroptosis as a PAH regulating pathway via its ability to modulate lung lipid metabolism, repress pathogenic complement activation, dampen interstitial macrophage infiltration, and restore the lung cellular environment.

Association of Longitudinal Activity Measures and Diabetes Risk: An Analysis From the National Institutes of Health All of Us Research Program.

CONTEXT: Prior studies of the relationship between physical activity and incident type 2 diabetes mellitus (T2DM) relied primarily on questionnaires at a single time point. OBJECTIVE: We sought to investigate the relationship between physical activity and incident T2DM with an innovative approach using data from commercial wearable devices linked to electronic health records in a real-world population. METHODS: Using All of Us participants' accelerometer data from their personal Fitbit devices, we used a time-varying Cox proportional hazards models with repeated measures of physical activity for the outcome of incident T2DM. We evaluated for effect modification with age, sex, body mass index (BMI), and sedentary time using multiplicative interaction terms. RESULTS: From 5677 participants in the All of Us Research Program (median age 51 years; 74% female; 89% White), there were 97 (2%) cases of incident T2DM over a median follow-up period of 3.8 years between 2010 to 2021. In models adjusted for age, sex, and race, the hazard of incident diabetes was reduced by 44% (95% CI, 15%-63%; P = 0.01) when comparing those with an average daily step count of 10 700 to those with 6000. Similar benefits were seen comparing groups based on average duration of various intensities of activity (eg, lightly active, fairly active, very active). There was no evidence for effect modification by age, sex, BMI, or sedentary time. CONCLUSION: Greater time in any type of physical activity intensity was associated with lower risk of T2DM irrespective of age, sex, BMI, or sedentary time.

Neutrophil trafficking to the site of infection requires Cpt1a-dependent fatty acid ß-oxidation.

Cellular metabolism influences immune cell function, with mitochondrial fatty acid ß-oxidation and oxidative phosphorylation required for multiple immune cell phenotypes. Carnitine palmitoyltransferase 1a (Cpt1a) is considered the rate-limiting enzyme for mitochondrial metabolism of long-chain fatty acids, and Cpt1a deficiency is associated with infant mortality and infection risk. This study was undertaken to test the hypothesis that impairment in Cpt1a-dependent fatty acid oxidation results in increased susceptibility to infection. Screening the Cpt1a gene for common variants predicted to affect protein function revealed allele rs2229738_T, which was associated with pneumonia risk in a targeted human phenome association study. Pharmacologic inhibition of Cpt1a increases mortality and impairs control of the infection in a murine model of bacterial pneumonia. Susceptibility to pneumonia is associated with blunted neutrophilic responses in mice and humans that result from impaired neutrophil trafficking to the site of infection. Chemotaxis responsible for neutrophil trafficking requires Cpt1a-dependent mitochondrial fatty acid oxidation for amplification of chemoattractant signals. These findings identify Cpt1a as a potential host determinant of infection susceptibility and demonstrate a requirement for mitochondrial fatty acid oxidation in neutrophil biology.

Association of step counts over time with the risk of chronic disease in the All of Us Research Program.

The association between physical activity and human disease has not been examined using commercial devices linked to electronic health records. Using the electronic health records data from the All of Us Research Program, we show that step count volumes as captured by participants' own Fitbit devices were associated with risk of chronic disease across the entire human phenome. Of the 6,042 participants included in the study, 73% were female, 84% were white and 71% had a college degree, and participants had a median age of 56.7 (interquartile range 41.5-67.6) years and body mass index of 28.1 (24.3-32.9) kg m-2. Participants walked a median of 7,731.3 (5,866.8-9,826.8) steps per day over the median activity monitoring period of 4.0 (2.2-5.6) years with a total of 5.9 million person-days of monitoring. The relationship between steps per day and incident disease was inverse and linear for obesity (n = 368), sleep apnea (n = 348), gastroesophageal reflux disease (n = 432) and major depressive disorder (n = 467), with values above 8,200 daily steps associated with protection from incident disease. The relationships with incident diabetes (n = 156) and hypertension (n = 482) were nonlinear with no further risk reduction above 8,000-9,000 steps. Although validation in a more diverse sample is needed, these findings provide a real-world evidence-base for clinical guidance regarding activity levels that are necessary to reduce disease risk.