Development Of Right Heart Failure Research Articles

The Right Ventricular-Arterial Compliance Index: A Novel Hemodynamic Marker to Predict Right Heart Failure Following Left Ventricular Assist Device.

The development of right heart failure (RHF) in patients with advanced heart failure following left ventricular assist device (LVAD) implantation remains difficult to predict. We proposed a novel composite hemodynamic index-the right ventricular-arterial compliance index (RVACi), derived from pulmonary artery pulse pressure (PAPP), ejection time (ET), heart rate (HR), and cardiac output (CO), with and expressed as mm Hg·s/L. We then conducted a retrospective, single-center analysis comparing the predictive value of RVACi for the development of RHF or unplanned right ventricular (RV) mechanical circulatory support following LVAD implantation against existing hemodynamic indices. One hundred patients were enrolled after screening 232 patients over a 10 year period, with 74 patients having complete hemodynamic data for RVACi calculation. There was good correlation between pulmonary arterial capacitance (R² = 0.48) and pulmonary vascular resistance (R² = 0.63) with RVACi, but not RV stroke work index or pulmonary artery pulsatility index. Reduced baseline RVACi (52 ± 23 vs. 92 ± 55 mm Hg·s/L; p = 0.02) was the strongest hemodynamic predictor of unplanned RV mechanical circulatory support requirement in patients following LVAD insertion. Composite pulsatile hemodynamic indices including RVACi may provide additional insight over existing hemodynamic indices for the prediction of RHF and need for RV mechanical circulatory support.

Dapagliflozin alleviates right heart failure by promoting collagen degradation by reducing ROS levels

BackgroundRight ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms. MethodsWe conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-β) to investigate the effect of DAPA. ResultsIn vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels. ConclusionsIn summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.

A case of pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension - a happily completed odyssey

Chronic thromboembolic pulmonary hypertension is a rare condition that is usually a consequence of prior acute pulmonary embolism. It is caused by persistent obstruction of pulmonary arteries by organized thrombi resulting in redistribution of blood flow and secondary pulmonary microvascular remodelling. Thus, pulmonary vascular resistance and pulmonary artery pressure are increased leading to right ventricle pressure overload, development of right heart failure and death. In eligible patients pulmonary endarterectomy is the standard of care and it can result in complete normalization of haemodynamics and right ventricular morphology and function. We present the case of a patient with chronic thromboembolic pulmonary hypertension with severe right ventricular dilation and dysfunction and refractory heart failure. After successful pulmonary endarterectomy we observed almost complete normalization of hemodynamics and restoration of right ventricular dimensions and function, as well as significant clinical improvement.

Effect of Anesthesia Induction on Cardiac Hemodynamics in Patients Undergoing Durable Left Ventricular Assist Device Implantation: The EACH-LVAD Study.

Right ventricular (RV) dysfunction is common after left ventricular assist device (LVAD) implantation leading to clinical right heart failure (RHF) associated with worsened survival and quality of life. It is likely that intraoperative events such as anesthesia induction play a role in the development or unmasking of RV dysfunction in addition to known effects from hemodynamic changes that occur after LVAD implantation. The EACH-LVAD Study is a prospective, single-center, single-arm, observational cohort study of adult patients with advanced heart failure undergoing durable LVAD implantation with standard anesthesia induction. Intraoperative RV hemodynamics via central venous pressure, mean pulmonary artery pressure, pulmonary artery pulsatility index, and vasoactive-inotropic score (a simple weighted summation of standardized drug doses) and echocardiographic parameters (RV fractional area change, RV area in diastole, RV basal diameter, septum position, RV function, tricuspid regurgitation) were measured and compared at prespecified timepoints, including postinduction. Postoperative clinical RHF was determined based on published definitions. Forty-two patients receiving a first-time LVAD were included between September 2017 and March 2019. Propofol-based induction was used in 31 patients and etomidate-based induction in eight patients. A significant increase in central venous pressure (CVP; p < 0.001), mean pulmonary artery pressure (mPAP; p < 0.001), and vasoactive inotropic score (VIS; p < 0.001) with associated decrease in pulmonary artery pulsatility index (PAPi; p < 0.001) was observed. Right ventricular function worsened throughout. Right heart failure occurred in 70% of patients. Propofol-based induction was not associated with a higher risk of RHF (relative risk [RR], 1.01 [95% confidence interval {CI}, 0.64-1.61]). The EACH-LVAD study demonstrates an effect of anesthesia induction on worsened RV hemodynamics and echocardiographic changes which may have an effect on the development of RHF.

Clinical Overview of Chronic Obstructive Pulmonary Disease Patients with Myocardial Perfusion Defect

Abstract: Background: Increased hospitalization and death rates up to 2-3 times greater due to cardiovascular diseases have been reported in Chronic Obstructive Pulmonary Disease (COPD) cases. Inflammation, neurohumoral activation, and increased oxidative stress are involved in the etiopathogenesis of both disease groups. Objective: The study aimed to retrospectively evaluate the patients with COPD with perfusion defects (ischemia/infarct) in myocardial perfusion scintigraphy and investigate the clinical features of these patients. Materials and Methods: Patients with COPD were included in the study by examining the files of 196 patients who had perfusion defects by performing myocardial perfusion scintigraphy (MPS) in the Nuclear Medicine Clinic of our hospital between January 2019-2021. Demographic data, comorbidities, areas of involvement in myocardial perfusion scintigraphy, pulmonary function test (PFT), smoking history, modified Medical Research Council (mMRC) score, pulse oxygen saturation, and echocardiography (ECHO) data were recorded. Results: COPD was detected in 6 (3%) of 196 patients. All of these cases were male and the age range was 67.2 ± 7.4 years. All 6 cases were male, and the mean age was 67.2 ± 7.4 years. They all had a history of heavy smoking (52.5 ± 30.9 packs/year). The mean forced expiratory volume in 1 second (FEV1) was 49.6 ± 8.9%, and pulse oxygen saturation was 93.2 ± 3.3%. In ECHO, systolic pulmonary artery pressure (PAPs) was higher than normal in 2 patients; one had advanced mitral insufficiency and heart failure. In the MPS of 4 patients, an infarct was observed in the area supplied by the right coronary artery (RCA). While there was no comorbid disease in 2 patients, comorbid diseases were present in 4. There was no significant difference between the non-COPD group and the COPD group in terms of age and gender. In the non-COPD group, the most common LAD localized defect (35.3%) and RCA localized defect (23.2%) were detected, while the most common RCA defect (50%) was found in the COPD group. However, it was not statistically significant due to the small sample size. Conclusion: In COPD cases, it was determined that infarct developed in the male gender, advanced age and advanced stage, and especially in the area fed with RCA if exposed to heavy smoking. It is considered that the ischemic changes observed in RCA in COPD may have a role in the development of right heart failure.

The Role of Glutamine and Glutaminase in Pulmonary Hypertension.

Pulmonary hypertension (PH) refers to a clinical and pathophysiological syndrome in which pulmonary vascular resistance and pulmonary arterial pressure are increased due to structural or functional changes in pulmonary vasculature caused by a variety of etiologies and different pathogenic mechanisms. It is followed by the development of right heart failure and even death. In recent years, most studies have found that PH and cancer shared a complex common pathological metabolic disturbance, such as the shift from oxidative phosphorylation to glycolysis. During the shifting process, there is an upregulation of glutamine decomposition driven by glutaminase. However, the relationship between PH and glutamine hydrolysis, especially by glutaminase is yet unclear. This review aims to explore the special linking among glutamine hydrolysis, glutaminase and PH, so as to provide theoretical basis for clinical precision treatment in PH.

Pulmonary Hypertension in Hispanics: An Update on Treatment Options and Possible Causes

Pulmonary arterial hypertension, a form of pulmonary hypertension (PH), is a rare but serious disease. This condition carries significantly increased risk of morbidity and mortality, associated with progressive elevations of pulmonary pressures and the subsequent development of right heart failure. PAH can also be very difficult to diagnose primarily because the initial symptom of shortness of breath can be very nonspecific and similar to other diseases. There are certain medications used to target obesity that have been associated with the development of pulmonary hypertension. Aminorex, commonly used in Europe in the 1960s, has been grossly tied with PAH. Additionally, Flenfluramine both on its own and used in combination with Phentermine, as appetite-suppressant medications, were associated with Primary Pulmonary Hypertension and valvulopathies. We believe the widespread use of weight loss medications in Latin America remains a risk factor for PH development in the Hispanic population. The NIH and the REVEAL registries in the United States provide the most information for different races/ethnicities in patients with the diagnosis of PAH. Both NIH and the REVEAL registries in the United States show a lower prevalence of PH than the expected prevalence of 11.5% in the Hispanic population. The underdiagnosis of PH in the Hispanic population can be explained by several causes such as lack of awareness of disease, access to healthcare, and tolerance to symptoms. Remarkable efforts in medicine have been made to better treat patients with this condition in the past few years, with the introduction of combination therapy in treatment-naive patients, which has changed the guidelines for treatment of PAH. Furthermore, recent clinical trials have shown promissory results with initiation of dual or even triple therapy instead of a step up approach in therapeutics. However, the majority of these therapies are indicated for PAH and PH related to connective tissue disease and come with a high financial burden to patients, especially minority patients such as Hispanics.

Potts Shunt in Children With Familial Primary Pulmonary Hypertension: A Case Report and Brief Literature Review

Introduction: The primary concern about Familial Pulmonary Arterial Hypertension (FPAH) is the development of right heart failure, which ultimately leads to sudden death. Despite recent advances in pharmacological therapy, the mortality rate in children is still high, emphasizing the importance of novel treatments. Moreover, there is still no definitive treatment for children with severe pulmonary hypertension. The consequences of right heart failure led to the proposal of a surgical approach, the Potts shunt, to decompress the right ventricle, providing shunting of deoxygenated blood to lower extremities and improving overall cardiac output. This surgical technique creates an anastomosis between the left pulmonary artery and the descending aorta, providing a palliative treatment to off-load the right ventricle. Case Presentation: We report an 11-year-old girl with familial pulmonary arterial hypertension and right ventricular failure who benefited from a Potts shunt with good mid-term results. The patient was diagnosed at the age of 5 when she had a history of fainting and persistent syncope. The patient was under medical treatment therapy with bosentan, sildenafil, acetylsalicylic acid, and warfarin for six years. The results of molecular genetic testing, which was confirmed with direct sequencing of the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) gene, revealed a heterozygous pathogenic mutation. Since she was diagnosed with Pulmonary Arterial Hypertension (PAH), she lost her grandmother, an aunt, and father because of PAH. Her 14-year-old sister also had mutated the BMPR2 gene without developing FPAH. Conclusions: The Potts shunt provides an interventional step for palliation of patients with familial pulmonary hypertension and severe right heart failure refractory to medical treatment. It opens the door to the possibility of lung transplantation in the future. We did not see any complications within 6 years after placing the Potts shunt.

Critical Care Management of Decompensated Right Heart Failure in Pulmonary Arterial Hypertension Patients - An Ongoing Approach.

Despite substantial advancements in diagnosis and specific medical therapy in pulmonary arterial hypertension patients’ management, this condition continues to represent a major cause of mortality worldwide. In pulmonary arterial hypertension, the continuous increase of pulmonary vascular resistance and rapid development of right heart failure determine a poor prognosis. Against targeted therapy, patients inexorable deteriorate over time. Pulmonary arterial hypertension patients with acute right heart failure who need intensive care unit admission present a complexity of the disease pathophysiology. Intensive care management challenges are multifaceted. Awareness of algorithms of right-sided heart failure monitoring in intensive care units, targeted pulmonary hypertension therapies, and recognition of precipitating factors, hemodynamic instability and progressive multisystem organ failure requires a multidisciplinary pulmonary hypertension team. This paper summarizes the management strategies of acute right-sided heart failure in pulmonary arterial hypertension adult cases based on recently available data.

Comprehensive identification of signaling pathways for idiopathic pulmonary arterial hypertension.

Whole exome sequencing (WES) was used in the research of familial pulmonary arterial hypertension (FPAH). CAV1 and KCNK3 were found as two novel candidate genes of FPAH. However, few pathogenic genes were identified in idiopathic pulmonary arterial hypertension (IPAH). We conducted WES in 20 unrelated IPAH patients who did not carry the known PAH-pathogenic variants among BMPR2, CAV1, KCNK3, SMAD9, ALK1, and ENG. We found a total of 4,950 variants in 3,534 genes, including 4,444 single-nucleotide polymorphisms and 506 insertions/deletions (InDels). Through the comprehensive and multilevel analysis, we disclosed several novel signaling cascades significantly connected to IPAH, including variants related to cadherin signaling pathway, dilated cardiomyopathy, glucose metabolism, immune response, mucin-type O-glycosylation, phospholipase C (PLC)-activating G protein-coupled receptor (GPCR) signaling pathway, vascular contraction and generation, and voltage-dependent Ca2+ channels. We also conducted validation studies in five mutant genes related to PLC-activating GPCR signaling pathway potentially involved in intracellular calcium regulation through Sanger sequencing for mutation accuracy, qRT-PCR for mRNA stability, immunofluorescence for subcellular localization, Western blotting for protein level, Fura-2 imaging for intracellular calcium, and proliferation analysis for cell function. The validation experiments showed that those variants in CCR5 and C3AR1 significantly increased the rise of intracellular calcium and the variant in CCR5 profoundly enhanced proliferative capacity of human pulmonary artery smooth muscle cells. Thus, our study suggests that multiple genetically affected signaling pathways take effect together to cause the formation of IPAH and the development of right heart failure and may further provide new therapy targets or putative clues for the present treatments such as limited therapeutic effectiveness of Ca2+ channel blockers.

Pulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab

BackgroundPulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking.Case presentationA 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD).ConclusionPTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes.

Pulmonary valve replacement in patients with corrected tetralogy of Fallot.

Introduction: Development of pulmonary insufficiency in patients with surgically corrected tetralogy of Fallot (TOF) may lead to severe right heart failure with serious consequences. We herein present our experience with pulmonary valve replacement (PVR) in these patients. Methods: From 2005-2013, 99 consecutive patients (71 males/28 females, mean age 38±8 years), underwent PVR after 7 to 40 (mean 29 ± 8) years from the initial correction. Seventy nine of the symptomatic patients presented in NYHA II, 14 in III and 2 in IV. All underwent PVR with a stented bioprosthetic valve, employing a beating heart technique with normothermic extracorporeal circulation support. Concomitant procedures included resection of aneurysmal outflow tract patches (n = 37), tricuspid valve annuloplasty (n = 36), augmentation of stenotic pulmonary arteries (n = 9), maze procedure (n = 2) and pulmonary artery stenting (n = 4). Results: There were 2 perioperative deaths (2%). One patient developed sternal dehiscence requiring rewiring. Median ICU and hospital stay was 1 and 7 days respectively. Postoperative echocardiography at 6 and 12 months showed excellent bioprosthetic valve performance, significant decrease in size of the right cardiac chambers and reduction of tricuspid regurgitation (TR) in the majority of the patients. At mean follow-up of 3.6 ± 2 years, all surviving patients remain in excellent clinical condition. Conclusion: Probability of reoperation for pulmonary insufficiency in patients with surgically corrected TOF increases with time and timely PVR by preventing the development of right heart failure is crucial for long-term survival. Current bioprosthetic valve technology in combination with the beating heart technique provides excellent immediate and short-term results. Further follow-up is necessary to evaluate long-term outcome.

Comprehensive Echocardiographic Assessment of the Right Ventricle in Murine Models.

BackgroundNon-invasive high-resolution echocardiography to evaluate cardiovascular function of small animals is increasingly being used due to availability of genetically engineered murine models. Even though guidelines and standard values for humans were revised by the American Society of Echocardiography, evaluations on murine models are not performed according to any standard protocols. These limitations are preventing translation of preclinical evaluations to clinical meaningful conclusions. We have assessed the right heart of two commonly used murine models according to standard clinical guidelines, and provided the practical guide and sample values for cardiac assessments.MethodsRight heart echocardiography evaluations of CD1 and C57BL/6 mice were performed under 1–3% isoflurane anesthesia using Vevo® 2100 Imaging System with a high-frequency (18–38 MHz) probe (VisualSonics MS400). We have provided a practical guide on how to image and assess the right heart of a mouse which is frequently used to evaluate development of right heart failure due to pulmonary hypertension.ResultsOur results show significant differences between CD1 and C57BL/6 mice. Right ventricle structural assessment showed significantly larger (p < 0.05) size, and pulmonary artery diameter in CD1 mice (n = 11) compared to C57BL/6 mice (n = 15). Right heart systolic and diastolic functions were similar for both strains.ConclusionOur practical guide on how to image and assess the right heart of murine models provides the first comprehensive values which can be used for preclinical research studies using echocardiography. Additionally, our results indicate that there is a high variability between mouse species and experimental models should be carefully selected for cardiac evaluations.

Predictors of survival following trans-catheter aortic valve closure for left ventricular assist device associated aortic insufficiency.

This study sought to assess the long-term clinical benefits and predictors of survival of trans-catheter aortic valve closure in left ventricular assist device (LVAD) patients. LVADs have been shown to increase survival and quality of life in patients with end-stage heart failure. However, severe aortic insufficiency (AI) can develop in up to 50% of patients at 12 months resulting in significant morbidity and mortality. Trans-catheter treatment of LVAD associated AI has emerged as a potential alternative to surgical treatment. We conducted a retrospective analysis of all patients undergoing trans-catheter aortic valve closure using an Amplatzer Multi-Fenestrated Septal Occluder "Cribriform" device to assess potential clinical and procedural factors associated with survival. Student's t-tests were used to compare baseline patient demographics and procedural characteristics, as well as patient outcomes immediately post procedure and at 6 months. A P-value of less than 0.05 was considered statistically significant. A total of 10 patients (70% male, median age 59 years) were included. Technical success was accomplished in 100% of patients with a 6 month survival rate of 30% (3/10). Compared with survivors, non-survivors had a higher rate of pre-procedural clinical co-morbidities, an increased likelihood of right ventricular failure, and received larger occluder devices. Trans-catheter aortic valve closure successfully treats late severe AI in LVAD patients, however, the presence or development of right heart failure portends a worse prognosis. Further studies are needed to investigate the factors involved in the development of right ventricular failure, and potential treatment, in patients undergoing trans-catheter aortic valve closure.

Abstract 9783: Predictors of Survival in Patients Undergoing Trans-Catheter Aortic Valve Closure for Significant Left Ventricular Assist Device Associated Aortic Insufficiency

Introduction: Left ventricular assist devices (LVADs) have been shown to increase survival and quality of life in patients with end-stage congestive heart failure. However, severe aortic insufficiency (AI) can develop in up to 50% of patients with LVADs at 12 months resulting in significant morbidity and mortality. Trans-catheter treatment of LVAD associated AI has emerged as a potential alternative to surgical treatment, but long term clinical benefits are yet to be determined. Methods: We conducted a retrospective analysis of all patients undergoing trans-catheter aortic valve closure using an Amplatzer Multi-Fenestrated Septal Occluder “Cribiform” device (AGA Medical, Plymouth, Minnesota) at our institution between September 2011 and September 2013 to assess potential clinical and procedural factors associated with survival. Unpaired student’s t-tests were used to compare baseline patient demographics and procedural characteristics, as well as patient outcomes immediately post procedure and at 6 months. A p-value of &lt;0.05 was considered statistically significant. Results: A total of 8 patients (75% male, median age 59 years) were included in this analysis. Technical success of the procedure including total cessation of AI without evidence of coronary compromise was accomplished in 100% of patients with a 6 month survival rate of 38% (3/8). Predictors of survival include the absence of significant co-morbidities such as chronic renal insufficiency, smaller occlusion device placement, and the absence of right heart failure (Table 1). Conclusions: Trans-catheter aortic valve closure successfully treats late severe AI in LVAD patients, however, the presence or development of right heart failure portends a worse prognosis. Further studies are needed to investigate the potential right ventricular failure in patients undergoing trans-catheter aortic valve closure.

Proteomic remodeling of proteasome in right heart failure

The development of right heart failure (RHF) is characterized by alterations of right ventricle (RV) structure and function, but the mechanisms of RHF remain still unknown. Thus, understanding the RHF is essential for improved therapies. Therefore, identification by quantitative proteomics of targets specific to RHF may have therapeutic benefits to identify novel potential therapeutic targets. The objective of this study was to analyze the molecular mechanisms changing RV function in the diseased RHF and thus, to identify novel potential therapeutic targets. For this, we have performed differential proteomic analysis of whole RV proteins using two experimental rat models of RHF. Differential protein expression was observed for hundred twenty six RV proteins including proteins involved in structural constituent of cytoskeleton, motor activity, structural molecule activity, cytoskeleton protein binding and microtubule binding. Interestingly, further analysis of down-regulated proteins, reveals that both protein and gene expressions of proteasome subunits were drastically decreased in RHF, which was accompanied by an increase of ubiquitinated proteins. Interestingly, the proteasomal activities chymotrypsin and caspase-like were decreased whereas trypsin-like activity was maintained. In conclusion, this study revealed the involvement of ubiquitin–proteasome system (UPS) in RHF. Three deregulated mechanisms were discovered: (1) decreased gene and protein expressions of proteasome subunits, (2) decreased specific activity of proteasome; and (3) a specific accumulation of ubiquitinated proteins. This modulation of UPS of RV may provide a novel therapeutic avenue for restoration of cardiac function in the diseased RHF.

Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Pulmonary hypertension (PH) is a common complication of advanced chronic obstructive pulmonary disease (COPD) and is defined by a mean pulmonary artery pressure (PAP) ≥ 25 mm Hg at rest in the supine position. Owing to its frequency, COPD is a common cause of PH; in fact, it is the second most frequent cause of PH, just after left heart diseases. PH is due to the elevation of pulmonary vascular resistance, which is caused by functional and morphological factors, chronic alveolar hypoxia being the most important. In COPD PH is generally mild to moderate, PAP usually ranging between 25 and 35 mm Hg in a stable state of the disease. A small proportion of COPD patients may present a severe or “disproportionate” PH with a resting PAP &gt; 35–40 mm Hg. The prognosis is particularly poor in these patients. In COPD PH worsens during exercise, sleep and severe exacerbations of the disease, and these acute increases in afterload may favour the development of right heart failure. The diagnosis of PH relies on Doppler echocardiography, and right heart catheterization is needed in a minority of patients. Treatment of PH in COPD relies on long-term oxygen therapy (≥16 h/day) which generally stabilizes or at least attenuates the progression of PH. Vasodilator drugs, which are commonly used in idiopathic pulmonary arterial hypertension, have rarely been used in COPD, and we lack studies in this field. Patients with severe PH should be referred to a specialist PH centre where the possibility of inclusion in a controlled clinical trial should be considered.

Reactive oxygen species as therapeutic targets in pulmonary hypertension

Pulmonary hypertension (PH) is characterized by a progressive elevation of pulmonary arterial pressure due to alterations of both pulmonary vascular structure and function. This disease is rare but life-threatening, leading to the development of right heart failure. Current PH treatments, designed to target altered pulmonary vascular reactivity, include vasodilating prostanoids, phosphodiesterase-5 inhibitors and endothelin-1 receptor antagonists. Although managing to slow the progression of the disease, these molecules still do not cure PH. More effective treatments need to be developed, and novel therapeutic strategies, targeting in particular vascular remodelling, are currently under investigation. Reactive oxygen species (ROS) are important physiological messengers in vascular cells. In addition to atherosclerosis and other systemic vascular diseases, emerging evidence also support a role of ROS in PH pathogenesis. ROS production is increased in animal models of PH, associated with NADPH oxidases increased expression, in particular of several Nox enzymes thought to be the major source of ROS in the pulmonary vasculature. These increases have also been observed in vitro and in vivo in humans. Moreover, several studies have shown either the deleterious effect of agents promoting ROS generation on pulmonary vasculature or, conversely, the beneficial effect of antioxidant agents in animal models of PH. In these studies, ROS production has been directly linked to pulmonary vascular remodelling, endothelial dysfunction, altered vasoconstrictive responses, inflammation and modifications of the extracellular matrix, all important features of PH pathophysiology. Altogether, these findings indicate that ROS are interesting therapeutic targets in PH. Blockade of ROS-dependent signalling pathways, or disruption of sources of ROS in the pulmonary vasculature, targeting in particular Nox enzymes, represent promising new therapeutic strategies in this disease.

Antioxidants for the Treatment of Patients with Severe Angioproliferative Pulmonary Hypertension?

Pathobiological mechanisms that contribute to pulmonary vasoconstriction, lung vascular remodeling, and the development of right heart failure include the generation of reactive oxygen and nitrogen species and the response of lung vascular and cardiac cells to these molecules. We review the information regarding oxidant stress balanced by antioxidant mechanisms and the role of oxidants and antioxidants in hypoxic pulmonary hypertension and their potential role in an animal model of severe pulmonary arterial hypertension (PAH). In human lung tissue from patients with idiopathic PAH, we find reduced superoxide dismutase activity and high expression of the oxidant stress markers nitrotyrosine and 8-OH-guanosine. In the Sugen 5416/chronic hypoxia model of PAH, lung tissue expression of nitrotyrosine and hemeoxygenase 1 (HO-1) is substantial, while HO-1 expression in the failing right ventricle is decreased. This model, based on administration of the VEGF receptor blocker Sugen 5416 and chronic hypoxia (Su/Hx), reproduces many of the characteristic features of severe angioobliterative human PAH. Treatment of Su/Hx rats with protandim, which nuclear factor erythroid-2 related factor (Nrf2)-dependently upregulates the expression of genes encoding antioxidant enzymes, protects against right heart failure without affecting angioobliterative PAH. In human severe PAH, patient survival is determined by the function of the stressed right ventricle; investigation of oxidative and nitrosative stresses and their potential contribution to right heart failure is necessary. Antioxidant therapeutic strategies may be of benefit in the setting of human severe PAH. Whether antioxidant strategies affect lung vascular remodeling and/or prevent right heart failure remains to be examined.

Idiopathic Constriction of the Fetal Ductus Arteriosus

Premature constriction or closure of the ductus arteriosus can occur during fetal life. It is a rare phenomenon and has been described secondary to medication or structural lesions or as idiopathic constriction. Premature closure of the ductus arteriosus can lead to progressive right heart dysfunction with tricuspid regurgitation, congestive heart failure, fetal hydrops, and intrauterine death. This series describes diagnosis of fetal ductus arteriosus constriction of unknown etiology in 3 cases, prenatal management, and outcomes. Constriction of the ductus arteriosus can be diagnosed prenatally with careful interrogation of the ductal arch using pulsed Doppler sonography and complete fetal echocardiography. Close monitoring is mandatory to rule out development of right heart failure and to determine the intervention time.