Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease

Fonseca, Guilherme Henrique Hencklain; Souza, Rogério; Salemi, Vera Maria Cury; Jardim, Carlos; Gualandro, Sandra Fátima Menosi

doi:10.1183/09031936.00134410

Cited by 235 publications

(261 citation statements)

References 30 publications

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“…118,127,[129][130][131] Among these complications, PH occurs in 6%-10% of adults with SCD, and the presence of PH is associated with significant increase in the risk of death in these patients. [132][133][134][135] Although the etiology of PH in patients with SCD is multifactorial, including pulmonary arterial hypertension (PAH), pulmonary venous hypertension, and chronic thromboembolic disease, data suggest that mortality in adults with SCD and PH is proportional to the severity of precapillary PH. 136 Transcriptome analysis, PH, and the hypoxic response in SCD Despite SCD's Mendelian inheritance, the clinical course of SCD patients is highly variable.…”

Section: Ph In Scdmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca 2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.Keywords: hypoxia, pulmonary hypertension, genetics. In the autumn of 2015 at the Lost Valley Ranch in Sedalia, Colorado, the 34th Grover Conference, on pulmonary circulation in the "omics" era, convened for a 4-day symposium to discuss contemporary scientific concepts in the genetics, genomics, proteomics, and epigenetics of pulmonary vascular diseases. This biannual meeting, sponsored by the American Thoracic Society and co-led this year by Drs. C. Gregory Elliot, Wendy K. Chung, D. Hunter Best, and Eric D. Austin, commemorates the perpetual and transformative scientific contributions of Dr. Robert Grover 1 to the fields of high-altitude medicine and pulmonary vascular disease. This review is part of an ongoing Pulmonary Circulation thematic series that aims to provide a synopsis of key concepts presented at this year's Grover Conference.Here, we summarize the discussions that constituted a section of the conference emphasizing novel genetic and molecular mechanisms underpinning "pulmonary vascular and ventricular dysfunction in the susceptible patient." To accomplish this, three concepts are reviewed in detail: the functional relevance of chronic hypoxia (CH), discovered through genomic analyses; novel molecular mechanisms and phenotypic signatures of pulmonary vascular disease in sickle cell disease; and hormonal regulation of vascular f...

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Section: Ph In Scdmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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“…5 Pulmonary arterial hypertension (PAH) is a common chronic pulmonary complication of SCD in autopsy studies 6,7 and has a prevalence ranging from 6% to 11% when measured by the gold standard, right heart catheterization. [8][9][10][11] Elevated tricuspid regurgitant jet velocity (TRV), an echocardiographic surrogate of pulmonary artery systolic pressure elevation, is associated with increased mortality in SCD, 12,13 and in a recent series where patients with elevated TRV had confirmatory right heart catheterization, pulmonary hypertension resulted in a 37% 6-year mortality rate. 10 Treatment of SCDassociated PAH is limited, and attempts at expanding accepted PAH treatments to this subset of patients has led to unexpected complications.…”

Section: Introductionmentioning

confidence: 99%

Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

et al. 2013

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Pulmonary hypertension is recognized as a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). We now report benchtop phenotyping from the explanted lungs of the first successful lung transplant in SCD. Pulmonary artery smooth muscle cells (PASMCs) cultured from the explanted lungs were analyzed for proliferate capacity, superoxide (O 2 • − ) production, and changes in key pulmonary arterial hypertension (PAH)-associated molecules and compared with non-PAH PASMCs. Upregulation of several pathologic processes persisted in culture in SCD lung PASMCs in spite of cell passage. SCD lung PASMCs showed growth factor-and serum-independent proliferation, upregulation of matrix genes, and increased O 2• − production compared with control cells. Histologic analysis of SCDassociated PAH arteries demonstrated increased and ectopically located extracellular matrix deposition and degradation of elastin fibers. Biomechanical analysis of these vessels confirmed increased arterial stiffening and loss of elasticity. Functional analysis of distal fifth-order pulmonary arteries from these lungs demonstrated increased vasoconstriction to an α1-adrenergic receptor agonist and concurrent loss of both endothelial-dependent and endothelial-independent vasodilation compared with normal pulmonary arteries. This is the first study to evaluate the molecular, cellular, functional, and mechanical changes in endstage SCD-associated PAH.

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“…The prevalence of elevated TRV using echocardiography is estimated to be 25-30% among SCA patients and 10-25% in those with genotype SC 6,8,11 . However, studies have reported that only about 6-11% of patients with TRV ≥ 2.5m/s on ECHO have confirmed pulmonary hypertension on right heart catheterization 12,13 . Notwithstanding, elevated TRV ≥ 2.5m/s in sickle cell patients has been significantly associated with decreased exercise tolerance and increased mortality estimated to be about 40% at 40 months of follow-up and is therefore considered an independent risk factor for death among these patients 6,14,15 .…”

Section: Introductionmentioning

confidence: 99%

Clinical and Laboratory Predictors of Elevated TRV In Sickle Cell Anaemia

Afriyie-Mensah

Dei‐Adomakoh

Forson

et al. 2018

JHOR

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Pulmonary hypertension (PH) has become an increasingly recognized complication in sickle cell anaemia (SCA) and is a major cause of morbidity and mortality. Though the burden of SCA in sub-Saharan Africa is high, there is paucity of data on SCA-associated PH with little or no attention given to it in routine patient care. The current study therefore sought to determine the prevalence of PH and its associated risk factors among adult patients with SCA. This was a cross-sectional study involving 76 clinically stable, hydroxyurea-naive participants. We obtained socio-demographic and clinical history. Measurement of Tricuspid Regurgitant jet Velocity (TRV) was obtained via transthoracic echocardiography and lung function was assessed using spirometry and pulse oximetry. Other investigations were complete blood counts, free plasma haemoglobin, serum urea and creatinine. Twenty-five (32.9%) of study participants had elevated TRV (≥ 2.5m/s) on Doppler echocardiography, which was suggestive of raised pulmonary artery systolic pressure.There were significant associations between elevated TRV and steady-state haemoglobin (p < 0.001), blood urea level (p = 0.030), presence of chronic leg ulcers (p = 0.043) and oxygen saturation (p < 0.001) and these may be identifiable and modifiable risk factors for selective screening with echocardiography in a resource poor setting.

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Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease

Cited by 235 publications

References 30 publications

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

Clinical and Laboratory Predictors of Elevated TRV In Sickle Cell Anaemia

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