Browsing by Subject "Pulmonary arterial hypertension"
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Item BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series)(Sage Journals, 2018-04) Frump, Andrea; Prewitt, Allison; de Caestecker, Mark P.; Medicine, School of MedicineDespite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor ( BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on the effects different BMPR2 mutation have on endothelial function, and whether there are qualitative differences between different BMPR2 mutations. We discuss evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and summarize limitations of the models that are used to study these effects. Finally, we discuss evidence that BMPR2-dependent effects on endothelial metabolism provides a unifying explanation for the many of the BMPR2 mutation-dependent effects that have been described in patients with HPAH.Item Cytokine profiling in pulmonary arterial hypertension: the role of redox homeostasis and sex(Elsevier, 2022) Rafikov, Ruslan; Rischard, Franz; Vasilyev, Mikhail; Varghese, Mathews V.; Yuan, Jason X-J; Desai, Ankit A.; Garcia, Joe G.; Rafikova, Olga; Medicine, School of MedicinePulmonary arterial hypertension (PAH) is a fatal disease with a well-established sexual dimorphism. Activated inflammatory response and altered redox homeostasis, both known to manifest in a sex-specific manner, are implicated in the pathogenic mechanisms involved in PAH development. This study aimed to evaluate the impact of sex and plasma redox status on circulating cytokine profiles. Plasma oxidation-reduction potential (ORP), as a substitute measure of redox status, was analyzed in male and female Group 1 PAH and healthy subjects. The profiles of 27 circulating cytokines were compared in 2 PAH groups exhibiting the highest and lowest quartile for plasma ORP, correlated with clinical parameters, and used to predict patient survival. The analysis of the PAH groups with the highest and lowest ORP revealed a correlation between elevated cytokine levels and increased oxidative stress in females. In contrast, in males, cytokine expressions were increased in the lower oxidative environment (except for IL-1b). Correlations of the increased cytokine expressions with PAH severity were highly sex-dependent and corresponded to the increase in PAH severity in males and less severe PAH in females. Machine learning algorithms trained on the combined cytokine and redox profiles allowed the prediction of PAH mortality with 80% accuracy. We conclude that the profile of circulating cytokines in PAH patients is redox- and sex-dependent, suggesting the vital need to stratify the patient cohort subjected to anti-inflammatory therapies. Combined cytokine and/or redox profiling showed promising value for predicting the patients' survival.Item Deciphering the Role of Mitochondrial Dysfunction in Pulmonary Arterial Hypertension(2024-06) Balachandar, Srimmitha; Aldred, Micheala A.; Graham, Brett H.; Zhang, Jie; Geraci, Mark W.; Machado, Roberto F.Pulmonary arterial hypertension (PAH) is a life-threatening vasculopathy caused by remodeling of pulmonary arterioles. It is unknown as to why some people are at more risk of developing PAH compared to others. Notably, while germline pathogenic variants in PAH genes are a strong driver of disease susceptibility, less than half of mutation carriers actually develop the disease, suggesting the need for additional triggers. Our previous studies have shown increased DNA damage and total reactive oxygen species (ROS) in cells from PAH patients and unaffected relatives, indicating a potential genetic component, leading to our hypothesis: Mitochondrial dysfunction is an independent genetically determined modifier of PAH susceptibility. Untargeted metabolomics (Metabolon) revealed abnormalities in the antioxidants, glutamate, urea, amino acid, galactose, and phospholipid metabolism pathways in the PAH Lymphoblastoid cells (LCLs) compared to controls. Intriguingly, the healthy relatives also had altered phospholipids, suggesting that it occurs independent of the disease. ROS analysis on LCLs from patients, their relatives and unrelated controls showed that the PAH LCLs had significantly higher levels of all ROS species compared to controls, with the highest in heritable PAH cells. LCLs from relatives clustered into two groups, one with increased mitochondrial (mt) ROS and hydrogen peroxide, the other comparable to controls. Seahorse assays showed that the LCLs with increased mtROS had reduced spare respiratory capacity indicative of dysfunctional electron transport chain (ETC); but no glycolytic switch. Cybrid models generated using the high and low ROS LCLs (H and L-donors) on a 143B nuclear background showed that the H-donors had mt respiration similar to L-donors, suggesting a functional ETC. However, these cells had significantly elevated mtROS, with reduced SOD2 protein (potentially a consequence of increased degradation), passed on from the parental LCLs to the recipient cybrids. PAH is a complex disease, and mutation status alone doesn’t determine disease susceptibility. LCLs from patients recapitulate some of the metabolomic abnormalities in lung vascular cells. Oxidative stress in LCLs extends to some unaffected relatives, suggesting this is an independent genetic trait that modifies PAH risk. Our study highlights the importance of identifying potential modifiers and the second hits in the pathogenesis of PAH.Item Defining the clinical validity of genes reported to cause pulmonary arterial hypertension(Elsevier, 2023) Welch, Carrie L.; Aldred, Micheala A.; Balachandar, Srimmitha; Dooijes, Dennis; Eichstaedt, Christina A.; Gräf, Stefan; Houweling, Arjan C.; Machado, Rajiv D.; Pandya, Divya; Prapa, Matina; Shaukat, Memoona; Southgate, Laura; Tenorio-Castano, Jair; ClinGen PH VCEP; Chung, Wendy K.; International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI); Medicine, School of MedicinePurpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. Methods: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. Results: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. Conclusion: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.Item Differential drug response in pulmonary arterial hypertension: The potential for precision medicine(Wiley, 2023-11-02) Miller, Elise; Sampson, Chinwuwanuju Ugo‐Obi; Desai, Ankit A.; Karnes, Jason H.; Medicine, School of MedicinePulmonary arterial hypertension (PAH) is a rare, complex, and deadly cardiopulmonary disease. It is characterized by changes in endothelial cell function and smooth muscle cell proliferation in the pulmonary arteries, causing persistent vasoconstriction, resulting in right heart hypertrophy and failure. There are multiple drug classes specific to PAH treatment, but variation between patients may impact treatment response. A small subset of patients is responsive to pulmonary vasodilators and can be treated with calcium channel blockers, which would be deleterious if prescribed to a typical PAH patient. Little is known about the underlying cause of this important difference in vasoresponsive PAH patients. Sex, race/ethnicity, and pharmacogenomics may also factor into efficacy and safety of PAH-specific drugs. Research has indicated that endothelin receptor antagonists may be more effective in women and there have been some minor differences found in certain races and ethnicities, but these findings are muddled by the impact of socioeconomic factors and a lack of representation of non-White patients in clinical trials. Genetic variants in genes such as CYP3A5, CYP2C9, PTGIS, PTGIR, GNG2, CHST3, and CHST13 may influence the efficacy and safety of certain PAH-specific drugs. PAH research faces many challenges, but there is potential for new methodologies to glean new insights into PAH development and treatment.Item Disparities in Clinical Outcomes Observed Within Electronic Health Record Data From a Statewide Cohort of Pulmonary Arterial Hypertension Patients(Wiley, 2025-01-13) Dalton, Rachel; Desai, Ankit A.; Jiao, Tianze; Duarte, Julio D.; Medicine, School of MedicineHealth disparities in patients with pulmonary arterial hypertension (PAH) have not been extensively reported in the United States. The aim of this project was to characterize the extent of demographic and socioeconomic disparities in clinical outcomes within a large, diverse PAH patient population. A retrospective, population-based study of electronic health record data from the OneFlorida Data Trust was completed. Adult patients seeking care within one of the 12 OneFlorida Network partner healthcare systems with a documented diagnosis of any form of pulmonary hypertension (PH), including PAH, via ICD-10 code were included. Social deprivation index and healthcare provider access scores were calculated from population-based centroids derived from patient home addresses. The primary outcome was all-cause mortality, with secondary outcomes including hospitalization, emergency department (ED) visits, and similar clinical outcomes in a combined cohort of patients with other forms PH. A total of 6379 patients were included in the PAH cohort, and 37,412 patients were included in the nonspecific PH cohort. PAH patients with the greatest social deprivation exhibited increased rates of ED visits and hospitalizations. Despite having similar rates of ED visits and hospitalizations compared to non-Hispanics, Hispanic PAH patients had markedly lower mortality rates. Similar associations were also observed in the combined cohort of 37,412 patients with other forms of PH. In conclusion, healthcare disparities exist in PAH outcomes across both demographic and socioeconomic boundaries. Patients identifying as Hispanic appear to have decreased rates of mortality compared to other races/ethnicities.Item Editorial: Pathophysiology and Pathogenic Mechanisms of Pulmonary Vascular Disease(Frontiers Media, 2022-03-18) Zhu, Jinsheng; Chen, Jiwang; Wang, Jian; Desai, Ankit A.; Black, Stephen M.; Tang, Haiyang; Medicine, School of MedicineItem The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: A systematic review and meta-analysis(Wolters Kluwer, 2018-03) Kuang, Hong-Yu; Wu, Yu-Hao; Yi, Qi-Jian; Tian, Jie; Wu, Chun; Shou, We Nian; Lu, Tie-Wei; Pediatrics, School of MedicineBACKGROUND: Oral bosentan has been widely applied in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). A systemic review and meta-analysis was conducted for a therapeutic evaluation of oral bosentan in both adult and pediatric patients with PAH-CHD. The acute responses and a long-term effect were respectively assessed in a comparison with baseline characteristics, and the improvement of exercise tolerance was analyzed. METHODS: PubMed, Medline, Embase, and Cochrane Central Register of clinical controlled trails or observational studies have been searched for a recording of bosentan effects on the PAH-CHD participants. For mortality and rate of adverse events (AEs), it was described in detail. Randomized-effects model or fixed-effects model was used to calculate different effective values with a sensitivity analysis. RESULTS: Seventeen studies were pooled in this review, and 3 studies enrolled the pediatric patients. Among all studies, 456 patients were diagnosed with PAH-CHD, and 91.7% were treated with oral bosentan. With a term less than 6 months of bosentan therapy, there existed a significant improvement in 6-minute walk distance (6MWD) and the World Health Organization functional class (WHO-FC), but no such differences in Borg dyspnea index scores (BDIs) and the resting oxygen saturation (SpO2). Although with a prolonged treatment, not only 6MWD and FC, but also the resting SpO2 and heart rate were changed for a better exercise capability. Additionally, compared with the basic cardiopulmonary hemodynamics, it showed a statistically significant difference in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi). Although a limitation of pooled studies with comparative outcomes of different terms, outcomes presented a lower WHO-FC which contributes to a success in a prolonged treatment. CONCLUSIONS: Bosentan in PAH-CHD is well established and still requires clinical trials for an identification of its efficiency on CHD patients for an optimized period lessening a serious complication and the common AEs.Item Food for Thought: The Emerging Role of Intestinal Microbiota in Pulmonary Arterial Hypertension(American Thoracic Society, 2022) Aldred, Micheala A.; Medicine, School of MedicineItem Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension(American Thoracic Society, 2020-06-01) Karnes, Jason H.; Wiener, Howard W.; Schwantes-An, Tae-Hwi; Natarajan, Balaji; Sweatt, Andrew J.; Chaturvedi, Abhishek; Arora, Amit; Batai, Ken; Nair, Vineet; Steiner, Heidi E.; Giles, Jason B.; Yu, Jeffrey; Hosseini, Maryam; Pauciulo, Michael W.; Lutz, Katie A.; Coleman, Anna W.; Feldman, Jeremy; Vanderpool, Rebecca; Tang, Haiyang; Garcia, Joe G.N.; Yuan, Jason X.J; Kittles, Rick; de Jesus Perez, Vinicio; Zamanian, Roham T.; Rischard, Franz; Tiwari, Hemant K.; Nichols, William C.; Benza, Raymond L.; Desai, Ankit A.; Medicine, School of MedicineRationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.