Right Ventricular Adaptation and Failure in Pulmonary Arterial Hypertension

Ryan, John; Huston, Jessica; Kutty, Shelby; Hatton, Nathan; Bowman, Lindsay C.; Tian, Lian; Herr, Julia E.; Johri, Amer M.; Archer, Stephen L.

doi:10.1016/j.cjca.2015.01.023

Cited by 155 publications

(119 citation statements)

References 124 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

Section: Discussionmentioning

confidence: 99%

“…J, Exercise tolerance decreased in DRV rats (n=6) compared with controls (n=11) and significantly improved in rats treated with mimic-126 (n=4) compared with DRV+vehicle (n=5 systolic function in PAH, RV adaptation to this increased afterload depends not only on the severity of pulmonary vascular disease but also on changes in myocardial metabolism, rate of myocardial hypertrophy and fibrosis, and adaptation of the capillary network. 36 This complex interplay likely explains the significant variability in RV adaptation to PAH between patients.In keeping with several previous studies in RV failure, 8,37 our study showed that, as in experimental PAH, 8,9 human RV failure is associated with decreased capillary density ( Figure 1A). Recently, Sutendra et al 8 proposed that, in the monocrotaline-induced PAH rat model, CRVH is characterized by a metabolic switch from oxidative phosphorylation to a glycolytic state, allowing the activation of HIF-1, increasing VEGF expression, and preserving angiogenesis.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

et al. 2015

View full text Add to dashboard Cite

R ight ventricular (RV) function is a major determinant of functional capacity and survival in pulmonary arterial hypertension (PAH) and other types of pulmonary hypertension.1 Although afterload is a prominent determinant for RV systolic function in PAH, there remains significant variability between patients with PAH in the ability of the RV to adapt to pressure overload and pulmonary resistance.2,3 The mechanisms accounting for this variability in RV adaptability to increased pulmonary load and for the transition to RV failure remain elusive. Despite the tremendous attention that left ventricular (LV) failure has received, RV failure has remained understudied at both the preclinical and clinical levels. 3 As a result, RV failure has emerged as an important research priority in the cardiopulmonary research field. Clinical Perspective on p 943Magnetic resonance imaging performed in patients with PAH has shown that the hypertrophied RV is ischemic 5 andBackground-Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. Methods and Results-We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31 + immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. Conclusions-RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH. Key Words: hypertension, pulmonary ◼ microRNAs ◼ microvessels ◼ pulmonary heart disease ◼ right ventricular failure © 2015 American Heart Assoc...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In PAH, obstructive remodeling of the pulmonary vasculature and reduced PA compliance increase pulmonary arterial pressures and right ventricular (RV) workload 4, 5. As PAH progresses, RV function declines, and many patients succumb from RV failure 6, 7. Although RV dysfunction is repeatedly identified as the major risk factor for mortality in PAH,8, 9, 10 the 4 classes of approved pulmonary hypertension medications primarily target the pulmonary vasculature, with little evidence of direct benefit to the RV.…”

Section: Introductionmentioning

confidence: 99%

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Prins

Tian

et al. 2017

JAHA

Self Cite

View full text Add to dashboard Cite

BackgroundPulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV‐targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin‐2 (JPH2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline‐induced PAH.Methods and ResultsImmunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t‐tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.ConclusionsMonocrotaline‐induced PAH causes RV‐specific derangement of microtubules marked by reduction in JPH2 and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t‐tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV‐directed therapy for PAH.

show abstract

“…1) Progressive increase in pulmonary artery pressure eventually leads to right ventricular hypertrophy (RVH), RV failure (RVF) and ultimately death.…”

mentioning

confidence: 99%

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

Xü

Liu

et al. 2017

Int. Heart J.

View full text Add to dashboard Cite

SummaryPulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular hypertrophy (RVH) and failure. Peroxisome proliferator-activated receptor γ (PPARγ), a member of nuclear receptors, has been proved to ameliorate PAH. However, its effect on PAH-induced right ventricular failure (RVF) remains unknown. Therefore, we investigated the therapeutic potential of PPARγ in preventing monocrotaline (MCT)-induced RV dysfunction. The PAH model was induced by MCT administration. Male rats were administered with MCT to develop PAH and RVF formed by approximately day 30. Significant increase in RV area, RVAW resulted in an ascending RV index. However, the LV function including EF, FS, and LVID did not change significantly. PPARγ agonist prevented PAH-induced RVF by preserving RV index and preventing RVH. PPARγ's beneficial effects seem to result from various factors, including anti-apoptosis, preservation RV index, reversal of inflammation, improvement of glucolipid metabolism, reduction of ROS. In a word, PPARγ agonist prevents the development of RVF.( Int Heart J 2017; 58: 948-956)

show abstract

Right Ventricular Adaptation and Failure in Pulmonary Arterial Hypertension

Cited by 155 publications

References 124 publications

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

Contact Info

Product

Resources

About