Jeffrey Annis’s research while affiliated with Vanderbilt University and other places

Reduced functional capacity and poor sleep quality are common in pulmonary arterial hypertension (PAH). Wearable devices are an emerging, user‐friendly tool to capture activity and sleep information. We aimed to determine whether Fitbit‐derived activity and sleep trends provide clinically meaningful information in patients with PAH. Our prospective observational study recruited patients with PAH from across the United States using remote enrollment strategies and in‐person efforts. Participants wore a Fitbit device for 12 weeks at baseline and a subgroup with 1‐year follow‐up. A matched control cohort was generated from the All of Us Research Program and we evaluated changes in patients with PAH compared to matched controls. Among 110 patients with baseline monitoring, average daily steps correlated with 6MWD (r = 0.61, p < 0.001) and percent rapid eye movement (REM) sleep (r = 0.28, p = 0.008). In 44 PAH participants who completed baseline and 1‐year monitoring, there was a group‐time interaction for percent light sleep (p = 0.024) and percent REM sleep (p = 0.034), which demonstrated that sleep quality worsened in patients with PAH over 1 year compared to matched controls. Average daily steps decreased in patients with PAH from 5200 [IQR 3212–7458] at baseline to 4651 [IQR 2912–6827] at 1 year (p = 0.008). In conclusion, our study demonstrated the potential clinical value of wearable devices by showing that activity and sleep quality are reduced in PAH compared to matched controls and these measures decline over time. Future studies should investigate if monitoring these health behaviors detects early functional decline and whether targeted interventions may improve outcomes.

Rationale: Incidence rates for pulmonary hypertension using diagnostic data in patients with cardiopulmonary disease are not known. Objectives: To determine incidence rates of, risk factors for, and mortality hazard associated with pulmonary hypertension among patients referred for transthoracic echocardiography. Methods: Retrospective cohort study using data from the Veterans Health Administration (1999-2020) and Vanderbilt University Medical Center (1994-2020). Pulmonary hypertension was defined as pulmonary artery systolic pressure >35mmHg with prevalent cases excluded. Heart failure and chronic obstructive pulmonary disease were the primary exposures of interest. The primary outcome was incident pulmonary hypertension. Secondarily, we examined mortality rate following incident diagnosis. Measurements and main results: We identified 245,067 VA patients (94% male, 20% Black) and 117,526 Vanderbilt patients (46% male, 11% Black) without pulmonary hypertension, of whom 38,882 VA patients and 8,061 Vanderbilt patients developed pulmonary hypertension. Only 18-19% of patients with echo-based pulmonary hypertension also had a diagnostic code. Hazard of pulmonary hypertension was 4-fold higher in patients with heart failure and chronic obstructive pulmonary disease compared to patients without either. Mortality rates increased from pulmonary artery systolic pressure of 35mmHg to 45mmHg then plateaued. Independent risk factors for incident pulmonary hypertension included older age, male sex, black race, and cardiometabolic comorbidities. Conclusions: Pulmonary hypertension incidence rates estimated by diagnostic data are higher than code-based rates. Heart failure and chronic obstructive pulmonary disease strongly associate with incident pulmonary hypertension. Pulmonary artery systolic pressure >45mmHg at diagnosis is associated with high mortality. New pulmonary hypertension on echocardiography is an important prognostic sign.

Background: Valine, leucine, and isoleucine are the branched amino acids (BCAA). Elevated BCAAs predict worse outcomes in several cardiovascular diseases with metabolic origins, but the role of BCAAs in pulmonary arterial hypertension (PAH) remains unclear. Moreover, the effects of BCAAs on the emerging lung-liver axis are unexplored. Methods: The effects of small molecule (BT2) activation of BCAA catabolism and a low BCAA diet were evaluated in monocrotaline rats. Multi-omics analyses of the lung and liver were conducted in the BT2 arm. Confocal microscopy evaluated hepatocyte nuclear size in rodents and humans with PAH. Human livers were subjected to proteomic analysis. Human single nucleotide polymorphisms (SNPs) associated with elevated BCAAs and their relationship with PAH were investigated in the BioVU database. Results: Proteomics and metabolomics profiling demonstrated BT2 restructured lung fat metabolism, which increased exercise capacity, reduced PAH severity, and improved RV function. A low BCAA diet also mitigated PAH severity and improved RV function. Pathological hepatic shear stress phenotypes induced by RV dysfunction (nuclear hypertrophy, AKT signaling, electron transport chain (ETC) homeostasis, and ceramide accumulation) were blunted by BT2. Human PAH livers partially phenocopied the rodent hepatic shear stress phenotype (nuclear enlargement, AKT activation, and ETC protein downregulation). Finally, patients harboring SNP rs117643180 had increased risk of PAH. Conclusion: Rodent and human data link altered BCAA catabolism to the pathogenic lung-liver axis in PAH.

Introduction: RV dysfunction (RVD) is one of the few cardiovascular conditions with unknown incidence rate (IR). We examined the rates, risk factors, and HF hospitalization hazard associated with incident RVD in pts referred for TTE. Methods: We extracted tricuspid regurgitant velocity (TRV) and TAPSE from all TTEs at Vanderbilt between 2010-2023. We selected the first TTE with normal RV function (TAPSE =/> 17mm) and a reported TRV. The primary outcome was new RVD (TAPSE < 17mm) and secondary outcome was time to HF hospitalization after second TTE. We used Poisson regression and multivariable cox models to estimate IRs and hazard ratios, adjusted for demographics, comorbidities, and TTE measures. We estimated a minimum IR in all pts with a baseline echo (Full Cohort) and a maximum IR among pts with a repeat TTE (Repeat TTE Cohort). Results: We identified 45,753 pts (63 years [IQR 50-72], 45% Male, 13% Black) with normal RV function at baseline, of whom 13,735 pts (30%) underwent a repeat TTE and 4,198 pts (10%) developed RVD. The IR of RVD in the Full Cohort was 3.2/100 person-yrs (95%CI 3.1-3.3) and 8.2 (95%CI 8.0-8.5) in the Repeat TTE Cohort. IRs were higher in pts with pulmonary hypertension vs without and increased with higher RVSP ( Figure 1) . Risk factors for incident RVD included HF (HR 1.88; 95%CI 1.75–2.03), AF (HR 1.54; 95%CI 1.44–1.65), and left-sided valvular disease (HR 1.68; 95%CI 1.53–1.85). Baseline RVSP was associated with TAPSE decline beginning near 35mmg ( Figure 2A ). Incident RVD was associated with increased hazard of HF hospitalization (HR 2.02; 95% CI 1.85-2.21). Hazard of HF hospitalization increased when TAPSE declined 5mm or greater ( Figure 2B ). Conclusions: RVD incidence is substantial among patients referred for TTE and warrants close monitoring when RVSP >35mmHg. Incident RVD and change in TAPSE >5mm were associated with increased hazard of HF hospitalization, even after adjustment for prevalent HF.

BACKGROUND Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined. METHODS Multiomics and physiological analyses evaluated how ferroptosis inhibition–modulated preclinical PAH. The impact of adeno-associated virus 1–mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension. RESULTS Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated that ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed that complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage–associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1- Acsl4 induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository. CONCLUSIONS Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.

Introduction: Incidence rates (IRs) of RV dysfunction (RVD) are unknown. We examined the rates, risk factors, and heart failure (HF) hospitalization hazard associated with incident RVD in patients referred for Transthoracic Echocardiogram (TTE). Methods: In this retrospective cohort study, we extracted tricuspid regurgitant velocity (TRV) and tricuspid annular systolic plane excursion (TAPSE) from TTEs at Vanderbilt (2010-2023). We followed patients from their earliest TTE with normal RV function≥17mm) and a reported TRV. The primary outcome was new RVD (TAPSE<17mm), and the secondary outcome was HF hospitalization after second TTE. Poisson regression and multivariable cox models estimated IRs and hazard ratios, adjusted for demographics, comorbidities, and TTE measures. Results: Among 45,753 patients (63 years [IQR 50-72], 45% Male, 13% Black) meeting inclusion criteria, 13,735 (30.1%) underwent a follow up TTE and 4,198 (9.2%) developed RVD. The IR of RVD in the full cohort was 3.2/100 person/years (95%CI 3.1-3.3) and 8.2 (95%CI 8.0-8.5) in the repeat TTE cohort. IRs increased with rising RVSP. Risk factors for incident RVD were most prominently HF (HR 1.88; 95%CI 1.75-2.03), left-sided valvular disease (HR 1.68; 95%CI 1.53-1.85), and other cardiovascular comorbidities. Baseline RVSP >35 mmHg associated with TAPSE decline over time. Incident RVD increased hazard of HF hospitalization (HR 2.02; 95%CI 1.85-2.21). Hazard of HF hospitalization increased when TAPSE declined by ≥5mm. Conclusions: RVD incidence is substantial among patients referred for TTE. Clinical monitoring is warranted if RVSP >35mmHg. Cardiovascular comorbidities drive RVD in this population. Incident RVD associates with increased hazard of HF hospitalization.

Rationale: Incidence rates for pulmonary hypertension using diagnostic data in patients with cardiopulmonary disease are not known. Objectives: To determine incidence rates of, risk factors for, and mortality hazard associated with pulmonary hypertension among patients referred for transthoracic echocardiography Methods: Retrospective cohort study using data from the Veterans Health Administration (1999-2020) and Vanderbilt University Medical Center (1994-2020). Pulmonary hypertension was defined as pulmonary artery systolic pressure >35mmHg with prevalent cases excluded. Heart failure and chronic obstructive pulmonary disease were the primary exposures of interest. The primary outcome was incident pulmonary hypertension. Secondarily, we examined mortality rate following incident diagnosis. Measurements and Main Results: We identified 245,067 VA patients (94% male, 20% Black) and 117,526 Vanderbilt patients (46% male, 11% Black) without pulmonary hypertension, of whom 38,882 VA patients and 8,061 Vanderbilt patients developed pulmonary hypertension. Only 18-19% of patients with echo-based pulmonary hypertension also had a diagnostic code. Hazard of pulmonary hypertension was 4-fold higher in patients with heart failure and chronic obstructive pulmonary disease compared to patients without either. Mortality rates increased from pulmonary artery systolic pressure of 35mmHg to 45mmHg then plateaued. Independent risk factors for incident pulmonary hypertension included older age, male sex, black race, and cardiometabolic comorbidities. Conclusions: Pulmonary hypertension incidence rates estimated by diagnostic data are higher than code-based rates. Heart failure and chronic obstructive pulmonary disease strongly associate with incident pulmonary hypertension. Pulmonary artery systolic pressure >45mmHg at diagnosis is associated with high mortality. New pulmonary hypertension on echocardiography is an important prognostic sign.