Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease

Tang, W.H. Wilson; Wilcox, Jennifer; Jacob, Miriam; Rosenzweig, Erika B.; Borlaug, Barry A.; Frantz, Robert P.; Hassoun, Paul M.; Hemnes, Anna R.; Hill, Nicholas S.; Horn, Evelyn M.; Singh, Harsimran; Systrom, David M.; Tedford, Ryan J.; Vanderpool, Rebecca; Waxman, Aaron B.; Xiao, Lei; Leopold, Jane A.; Rischard, Franz

doi:10.1161/circheartfailure.119.006363

Cited by 38 publications

(29 citation statements)

References 23 publications

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“…Pulmonary Hypertension (PH) is a progressive and devastating disease characterized by both vascular inflammation and structural remodeling (1)(2)(3)(4)(5)(6)(7). Current therapies primarily function as vasodilators and provide symptomatic relief but do not halt progressive remodeling (8).…”

Section: Introductionmentioning

confidence: 99%

Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension

Riddle

Kumar

et al. 2021

Front. Immunol.

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The recruitment and subsequent polarization of inflammatory monocytes/macrophages in the perivascular regions of pulmonary arteries is a key feature of pulmonary hypertension (PH). However, the mechanisms driving macrophage polarization within the adventitial microenvironment during PH progression remain unclear. We previously established that reciprocal interactions between fibroblasts and macrophages are essential in driving the activated phenotype of both cell types although the signals involved in these interactions remain undefined. We sought to test the hypothesis that adventitial fibroblasts produce a complex array of metabolites and proteins that coordinately direct metabolomic and transcriptomic re-programming of naïve macrophages to recapitulate the pathophysiologic phenotype observed in PH. Media conditioned by pulmonary artery adventitial fibroblasts isolated from pulmonary hypertensive (PH-CM) or age-matched control (CO-CM) calves were used to activate bone marrow derived macrophages. RNA-Seq and mass spectrometry-based metabolomics analyses were performed. Fibroblast conditioned medium from patients with idiopathic pulmonary arterial hypertension or controls were used to validate transcriptional findings. The microenvironment was targeted in vitro using a fibroblast-macrophage co-culture system and in vivo in a mouse model of hypoxia-induced PH. Both CO-CM and PH-CM actively, yet distinctly regulated macrophage transcriptomic and metabolomic profiles. Network integration revealed coordinated rewiring of pro-inflammatory and pro-remodeling gene regulation in concert with altered mitochondrial and intermediary metabolism in response to PH-CM. Pro-inflammation and metabolism are key regulators of macrophage phenotype in vitro, and are closely related to in vivo flow sorted lung interstitial/perivascular macrophages from hypoxic mice. Metabolic changes are accompanied by increased free NADH levels and increased expression of a metabolic sensor and transcriptional co-repressor, C-terminal binding protein 1 (CtBP1), a mechanism shared with adventitial PH-fibroblasts. Targeting the microenvironment created by both cell types with the CtBP1 inhibitor MTOB, inhibited macrophage pro-inflammatory and metabolic re-programming both in vitro and in vivo. In conclusion, coordinated transcriptional and metabolic reprogramming is a critical mechanism regulating macrophage polarization in response to the complex adventitial microenvironment in PH. Targeting the adventitial microenvironment can return activated macrophages toward quiescence and attenuate pathological remodeling that drives PH progression.

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Section: Introductionmentioning

confidence: 99%

Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension

Riddle

Kumar

et al. 2021

Front. Immunol.

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“…Particularly, AI methods have pioneered the development of robust and clinically relevant disease subtypes [79]. The concept of disease subtyping has been leveraged in treating many diseases [5,7], however, oncology is the prime example for this.…”

Section: Disease Subtypingmentioning

confidence: 99%

“…Since the introduction of this paradigm, the number of application areas in medicine and healthcare has rapidly increased, with oncology being the vanguard for its deployment [3]. Beyond that, recent works on cardiovascular diseases [4,5], type 2 diabetes [6] and neurodegenerative disorders, such as Alzheimer's disease [7] and Amyotrophic Lateral Sclerosis [8,9] have highlighted the growing relevance of precision medicine on the whole healthcare sector.…”

Section: Introductionmentioning

confidence: 99%

Artificial intelligence in early drug discovery enabling precision medicine

Boniolo

Dorigatti

Ohnmacht

et al. 2021

Expert Opinion on Drug Discovery

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Introduction: Precision medicine is the concept of treating diseases based on environmental factors, lifestyles, and molecular profiles of patients. This approach has been found to increase success rates of clinical trials and accelerate drug approvals. However, current precision medicine applications in early drug discovery use only a handful of molecular biomarkers to make decisions, whilst clinics gear up to capture the full molecular landscape of patients in the near future. This deep multi-omics characterization demands new analysis strategies to identify appropriate treatment regimens, which we envision will be pioneered by artificial intelligence. Areas covered: In this review, the authors discuss the current state of drug discovery in precision medicine and present our vision of how artificial intelligence will impact biomarker discovery and drug design. Expert opinion: Precision medicine is expected to revolutionize modern medicine; however, its traditional form is focusing on a few biomarkers, thus not equipped to leverage the full power of molecular landscapes. For learning how the development of drugs can be tailored to the heterogeneity of patients across their molecular profiles, artificial intelligence algorithms are the next frontier in precision medicine and will enable a fully personalized approach in drug design, and thus ultimately impacting clinical practice.

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“…Readers can refer to multiple papers discussing proper performance of RHC and analysis of hemodynamic data. 3,5,33…”

Section: Some Comments On Rhc Datamentioning

confidence: 99%

Pulmonary Hypertension by the Method of Paul Wood

Newman

2020

Chest

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A physiological approach to the analysis of hemodynamic data in pulmonary hypertension (PH) has the advantage of reducing the large number (well over 100) of potential causal illnesses into four simple mechanisms. A fifth condition is composed of mixtures of the four basic mechanisms. This approach was beautifully described by Paul Wood, the great cardiologist whose name is given to the units of pulmonary vascular resistance (PVR), Wood units. This approach uses well understood physiological contributions to pulmonary vascular pressure. It is powerful, the major uncertainty being in determination of the magnitude of each mechanism in patients that have mixed PH of several causes. It also makes sense of the occasionally awkward clustering of conditions in the clinical classification of the World Symposium, which omits pulmonary vasoconstriction, hyperkinetic states, and the highly prevalent condition of "mixed" PH. This method of analysis is described and demonstrated, much as Wood did in his writings. The method is useful in the office, the ICU, and in consultation. A basic message from this approach is that correct assessment requires measurement of each of the three major inputs, pulmonary arterial pressure (Ppa), pulmonary artery wedge pressure (Pwedge) and cardiac output (CO). Some cases also need left ventricular end diastolic pressure (LVEDP). Other data contributing to analysis will be discussed in each condition. A key to avoiding mistakes is to always remember that PH is simply an elevation in pressure and is not inherently diagnostic of cause.

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Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease

Cited by 38 publications

References 23 publications

Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension

Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension

Artificial intelligence in early drug discovery enabling precision medicine

Pulmonary Hypertension by the Method of Paul Wood

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