Distinct Platelet Ribonucleic Acid Signatures in Patients with Pulmonary Hypertension

Smits, Josien; Arkani, Mohammad; Veld, Sjors G J G In ‘t; Veld, Anna Egberdina Huis In 't; Sol, Nik; Groeneveldt, Joanne A.; Botros, Liza; Braams, Natalia J; Jansen, S; Ramaker, Jip; Zwaan, Kenn; Post, Edward P.; Nossent, Esther J.; Boonstra, Anco; Man, Frances S. de; Noordegraaf, Anton Vonk; Gomez-Arroyo, José; Best, Myron G.; Würdinger, Tom; Bogaard, Harm Jan

doi:10.1513/annalsats.202201-085oc

Cited by 3 publications

(4 citation statements)

References 41 publications

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“… 7 Recently, we showed that platelet RNA can function as a biomarker trove to detect and discriminate patients with PH from asymptomatic controls. 8 Blood platelets are circulating anucleated cell fragments that are classically known for their role in hemostasis and initiation of wound healing. Platelets contain premature messenger RNA and mediators of RNA transcription, splicing, and translation.…”

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confidence: 99%

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Discrimination Between Pre‐ and Postcapillary Pulmonary Hypertension Using Platelet RNA

Arkani

Kianzad

Jansen

et al. 2023

JAHA

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Background Appropriate treatment of pulmonary hypertension (PH) is critically dependent on accurate discrimination between pre‐ and postcapillary PH. However, clinical discrimination is challenging and frequently requires a right heart catheterization. Existing risk scores to detect postcapillary PH have suboptimal discriminatory strength. We have previously shown that platelet‐derived RNA profiles may have diagnostic value for PH detection. Here, we hypothesize that platelet‐derived RNAs can be employed to select unique biomarker panels for the discrimination between pre‐ and postcapillary PH. Methods and Results Blood platelet RNA from whole blood was isolated and sequenced from 50 patients with precapillary PH (with different PH subtypes) as well as 50 patients with postcapillary PH. RNA panels were calculated by ANOVA statistics, and classifications were performed using a support vector machine algorithm, supported by particle swarm optimization. We identified in total 4279 different RNAs in blood platelets from patients with pre‐ and postcapillary PH. A particle swarm optimization–selected RNA panel of 1618 distinctive RNAs with differential levels together with a trained support vector machine algorithm accurately discriminated patients with precapillary PH from patients with postcapillary PH with 100% sensitivity, 60% specificity, 80% accuracy, and 0.95 (95% CI, 0.86–1.00) area under the curve in the independent validation series (n=20). Conclusions This proof‐of‐concept study demonstrates that particle swarm optimization/support vector machine–enhanced classification of platelet RNA panels may be able to discriminate precapillary PH from postcapillary PH. This research provides a foundation for the development of a blood test with a high negative predictive value that would improve early diagnosis of precapillary PH and prevents unnecessary invasive testing in patients with postcapillary PH.

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confidence: 99%

“… 9 We and others have previously shown that platelets become “educated” by specific RNA splicing events during disease, 10 which allows detection of the presence of PH. 8 In this follow‐up study, we hypothesized that platelet RNA signatures might enable accurate blood‐based discrimination between pre‐ and postcapillary PH.…”

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confidence: 99%

Discrimination Between Pre‐ and Postcapillary Pulmonary Hypertension Using Platelet RNA

Arkani

Kianzad

Jansen

et al. 2023

JAHA

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“…The epigenetic mechanisms involved in the pathogenesis of PAH, specifically DNA methylation, histone modifications, and microRNAs may be a therapeutic potential [ 18 , 172 ]. Bromodomain and extra-terminal domain proteins are epigenetic modulators and bromodomain-containing protein 4 (BRD4) is involved in the inflammation of several major human lung diseases [ 173 ].…”

Section: Progress In Research and Treatment In Pah With The Potential...mentioning

confidence: 99%

“…Therefore, besides transthoracic echocardiography, the knowledge of typical ECG signs and the use of magnetic resonance imaging (MRI), as well as dual/energy computed tomography (CT), single photon emission CT and ventilation perfusion scans, could help to detect PAH earlier [ 16 , 17 ]. Moreover, the evaluation of a platelet RNA-based blood test improves the early diagnosis and clinical outcomes of PAH patients [ 18 ]. Early diagnosis is also crucial in the context of the prevention of chronic supraventricular tachyarrhythmias, such as atrial fibrillation (AF) and life-threatening ventricular fibrillation (VF).…”

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confidence: 99%

Connexin43, A Promising Target to Reduce Cardiac Arrhythmia Burden in Pulmonary Arterial Hypertension

Sykora,

Szeiffova Bacova,

Andelova

et al. 2024

IJMS

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While essential hypertension (HTN) is very prevalent, pulmonary arterial hypertension (PAH) is very rare in the general population. However, due to progressive heart failure, prognoses and survival rates are much worse in PAH. Patients with PAH are at a higher risk of developing supraventricular arrhythmias and malignant ventricular arrhythmias. The latter underlie sudden cardiac death regardless of the mechanical cardiac dysfunction. Systemic chronic inflammation and oxidative stress are causal factors that increase the risk of the occurrence of cardiac arrhythmias in hypertension. These stressful factors contribute to endothelial dysfunction and arterial pressure overload, resulting in the development of cardiac pro-arrhythmic conditions, including myocardial structural, ion channel and connexin43 (Cx43) channel remodeling and their dysfunction. Myocardial fibrosis appears to be a crucial proarrhythmic substrate linked with myocardial electrical instability due to the downregulation and abnormal topology of electrical coupling protein Cx43. Furthermore, these conditions promote ventricular mechanical dysfunction and heart failure. The treatment algorithm in HTN is superior to PAH, likely due to the paucity of comprehensive pathomechanisms and causal factors for a multitargeted approach in PAH. The intention of this review is to provide information regarding the role of Cx43 in the development of cardiac arrhythmias in hypertensive heart disease. Furthermore, information on the progress of therapy in terms of its cardioprotective and potentially antiarrhythmic effects is included. Specifically, the benefits of sodium glucose co-transporter inhibitors (SGLT2i), as well as sotatercept, pirfenidone, ranolazine, nintedanib, mirabegron and melatonin are discussed. Discovering novel therapeutic and antiarrhythmic strategies may be challenging for further research. Undoubtedly, such research should include protection of the heart from inflammation and oxidative stress, as these are primary pro-arrhythmic factors that jeopardize cardiac Cx43 homeostasis, the integrity of intercalated disk and extracellular matrix, and, thereby, heart function.

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Detection and localization of early- and late-stage cancers using platelet RNA

et al. 2022

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Distinct Platelet Ribonucleic Acid Signatures in Patients with Pulmonary Hypertension

Cited by 3 publications

References 41 publications

Discrimination Between Pre‐ and Postcapillary Pulmonary Hypertension Using Platelet RNA

Discrimination Between Pre‐ and Postcapillary Pulmonary Hypertension Using Platelet RNA

Connexin43, A Promising Target to Reduce Cardiac Arrhythmia Burden in Pulmonary Arterial Hypertension

Detection and localization of early- and late-stage cancers using platelet RNA

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