Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both.

Pulmonary hypertension describes a heterogeneous disease defined by increased pulmonary artery pressures, and progressive increase in pulmonary vascular resistance due to pathologic remodeling of the pulmonary vasculature involving pulmonary endothelial cells, pericytes, and smooth muscle cells. This process occurs under various conditions, and although these populations vary, the clinical manifestations are the same: progressive dyspnea, increases in right ventricular (RV) afterload and dysfunction, RV-pulmonary artery uncoupling, and right-sided heart failure with systemic circulatory collapse. The overall estimated 5-yr survival rate is 72% in highly functioning patients, and as low as 28% for those presenting with advanced symptoms. Metabolic theories have been suggested as underlying the pathogenesis of pulmonary hypertension with growing evidence of the role of mitochondrial dysfunction involving the major proteins of the electron transport chain, redox-related enzymes, regulators of the proton gradient and calcium homeostasis, regulators of apoptosis, and mitophagy. There remain more studies needed to characterize mitochondrial dysfunction leading to impaired vascular relaxation, increase proliferation, and failure of regulatory mechanisms. The effects on endothelial cells and resulting interactions with their microenvironment remain uncharted territory for future discovery. Additionally, on the basis of observations that the "plexigenic lesions" of pulmonary hypertension resemble the unregulated proliferation of tumor cells, similarities between cancer pathobiology and pulmonary hypertension have been drawn, suggesting interactions between mitochondria and angiogenesis. Recently, mitochondria targeting has become feasible, which may yield new therapeutic strategies. We present a state-of-the-art review of the role of mitochondria in both the pathobiology of pulmonary hypertension and potential therapeutic targets in pulmonary vascular processes.

Pulmonary hypertension in patients with interstitial lung disease.

Interstitial lung diseases (ILDs) comprise a broad and heterogeneous group of more than two hundred diseases with common functional characteristics. Their diagnosis and management require a multidisciplinary approach. This multidisciplinary approach involves the assessment of comorbid conditions including pulmonary hypertension (PH) that exerts a dramatic impact on survival. The current World Health Organization (WHO) classification of PH encompasses many of the interstitial lung diseases into WHO Group 3, while sarcoidosis, Pulmonary Langerhans Cell Histiocytosis and lymphangioleiomyomatosis are placed into WHO Group 5 as diseases with unclear or multifactorial mechanisms. Connective tissue diseases could span any of the 5 WHO groups based on the primary phenotype into which they manifest. Interestingly, several challenging phenotypes present with features that overlap between two or more WHO PH groups. Currently, PH-specific treatment is recommended only for patients classified into WHO Group 1 PH. The lack of specific treatment for other groups, including PH in the setting of ILD, reflects the poor outcomes of these patients. Thus, identification of the optimal strategy for ILD patients with PH remains an amenable need. This review article provides a brief overview of biomarkers indicative of vascular remodeling in interstitial lung disease, summarizes the current state of knowledge regarding patients with PH and ILD and highlights future perspectives that remain to be addressed.

S100A12 as a marker of worse cardiac output and mortality in pulmonary hypertension.

BACKGROUND AND OBJECTIVE: Molecular biomarkers are needed to refine prognostication and phenotyping of pulmonary hypertension (PH) patients. S100A12 is an emerging biomarker of various inflammatory diseases. This study aims to determine the prognostic value of S100A12 in PH. METHODS: Exploratory microarray analysis performed on peripheral blood mononuclear cells (PBMC) collected from idiopathic pulmonary fibrosis (IPF) patients suggested an association between S100A12 and both PH and mortality. So the current study was designed to evaluate for an association between S100A12 in peripheral blood collected from two well-phenotyped PH cohorts in two other centres to derive and validate an association between S100A12 protein serum concentrations and mortality. RESULTS: The majority of the patients in the discovery and validation cohorts were either World Health Organization (WHO) group 1 (pulmonary arterial hypertension (PAH)) or 3 (lung disease-associated) PH. In the discovery PH cohort, S100A12 was significantly increased in patients with PH (n = 51) compared to controls (n = 22) (29.8 vs 15.7 ng/mL, P < 0.001) and negatively correlated with cardiac output (r = -0.58, P < 0.001) in PH patients. When S100A12 data were pooled from both cohorts, PAH and non-PAH PH patients had higher S100A12 compared to healthy external controls (32.6, 30.9, 15.7 ng/mL; P < 0.001). S100A12 was associated with an increased risk in overall mortality in PH patients in both the discovery (n = 51; P = 0.008) and validation (n = 40; P < 0.001) cohorts. CONCLUSION: S100A12 levels are increased in PH patients and are associated with increased mortality.

Endovascular Treatment of a Large Iliac Vein Aneurysm and High-Flow Arteriovenous Fistula.

Aneurysms associated with arteriovenous fistulas (AVFs) are rare but can cause significant morbidity. They are often diagnosed after rupture, pain, or embolization. We describe a unique case of a 35-year-old woman with a large iliac vein aneurysm related to an acquired AVF incidentally discovered on ultrasound during pregnancy. She had a diagnosis of "idiopathic" pulmonary hypertension for several years. This report details the diagnosis and treatment with an arterial stent graft that was effective in decreasing the size of the venous aneurysm and reversing the systemic changes associated with the disease.

Chronic Right Heart Failure: Expanding Prevalence and Challenges in Outpatient Management.

Right heart failure is caused by right heart dysfunction resulting in suboptimal stroke volume to supply the pulmonary circulation. Therapeutic developments mean that patients with acute right heart failure survive to hospital discharge and live with chronic right heart failure. Chronic right heart failure management aims to reduce afterload, optimize preload, and support contractility, with the best evidence available in vascular targeted therapy for pulmonary arterial hypertension. However, the management of chronic right heart failure relies on adapting therapies for left ventricular heart failure to the right. We review right heart failure management in the ambulatory setting and its challenges.

Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

Pulmonary fibrosis is a progressive and often fatal condition that is believed to be partially orchestrated by macrophages. Mechanisms that control migration of these cells into and within the lung remain undefined. We evaluated the contributions of the semaphorin receptor, plexin C1 (PLXNC1), and the exocytic calcium sensor, synaptotagmin 7 (Syt7), in these processes. We evaluated the role of PLXNC1 in macrophage migration by using Boyden chambers and scratch tests, characterized its contribution to experimentally induced lung fibrosis in mice, and defined the mechanism for our observations. Our findings reveal that relative to control participants, patients with idiopathic pulmonary fibrosis demonstrate excessive monocyte migration and underexpression of PLXNC1 in the lungs and circulation, a finding that is recapitulated in the setting of scleroderma-related interstitial lung disease. Relative to wild type, PLXNC1-/- mouse macrophages are excessively migratory, and PLXNC1-/- mice show exacerbated collagen accumulation in response to either inhaled bleomycin or inducible lung targeted TGF-ß1 overexpression. These findings are ameliorated by replacement of PLXNC1 on bone marrow-derived cells or by genetic deletion of Syt7. These data demonstrate the previously unrecognized observation that PLXNC1 deficiency permits Syt7-mediated macrophage migration and enhances mammalian lung fibrosis.-Peng, X., Moore, M., Mathur, A., Zhou, Y., Sun, H., Gan, Y., Herazo-Maya, J. D., Kaminski, N., Hu, X., Pan, H., Ryu, C., Osafo-Addo, A., Homer, R. J., Feghali-Bostwick, C., Fares, W. H., Gulati, M., Hu, B., Lee, C.-G., Elias, J. A., Herzog, E. L. Plexin C1 deficiency permits synaptotagmin 7-mediated macrophage migration and enhances mammalian lung fibrosis.

The Assessment of the Right Heart Failure Syndrome.

The right heart failure (RHF) syndrome is a pathophysiologically complex state commonly associated with dysfunction of the right ventricle (RV). The normal RV is suited for its purposes of distributing venous blood to the low-resistance pulmonary circulation. Myriad stresses imposed upon it, though, can ultimately result in its failure, with the threat of cardiovascular collapse being the most dreaded outcome. Decreased cardiac output with increased central venous pressures are hemodynamic hallmarks of this highly morbid condition. Proper management of RHF is predicated on the accurate assessment of the key hemodynamic and clinical components signaling the syndrome that is the result of the failing RV. Appropriate use of diagnostic tools is paramount for understanding the key components of RV function: the preload state of the RV, its contractility, and the afterload burden placed on it. In making these assessments, it remains crucial to understand the limitations of these tools when managing RHF in the intensive care unit. An understanding of each of these components allows for the understanding of the physiology and the clinical presentation which can guide the use of therapies appropriately tailored to manage the condition.

The 'availability' bias: underappreciated but with major potential implications.

Many biases have been described that potentially introduce prejudice or a systemic error into a study that would favor one outcome versus another. One major source of bias has, so far, been underappreciated: the availability bias. When the study intervention is available to clinicians outside of the clinical trial, the trial could become biased to favor the control study arm. Clinicians may, consciously or unconsciously, use this intervention outside of the trial on patients whom they believe would benefit from the intervention, and enroll in the trial those patients for whom they do not feel strongly about the benefit of the intervention. The clinicians do not always share the equipoise of the study investigators. This could have major implications on the analysis of clinical trials, including the systematic reviews that originate from such trials.

Primary cardiac hospitalizations in pulmonary arterial hypertension: Trends and outcomes from 2001 to 2014.

BACKGROUND: Hospitalizations in pulmonary arterial hypertension (PAH) are common and are often for cardiac conditions. Using the National (Nationwide) Inpatient Sample (NIS), we examined characteristics and mortality of primary cardiac hospitalizations in PAH from 2001 to 2014. METHODS: Adult hospitalizations with any diagnosis code for PAH were identified. Primary cardiac disease was defined as a primary discharge diagnosis of congestive heart failure (CHF), pulmonary heart disease, coronary atherosclerosis, acute myocardial infarction, dysrhythmia, conduction disorder, cardiomyopathy or carditis, heart valve disorder, or cardiac arrest. Temporal trends, characteristics, and in-hospital mortality were analyzed. RESULTS: From 2001 to 2014, there were 207,095 hospitalizations in PAH, of which 100,509 (48.5%) carried a primary cardiac diagnosis. Most primary cardiac hospitalizations in PAH were for CHF, and pneumonia was the most common primary non-cardiac diagnosis. Over the study period, primary cardiac hospitalizations in PAH fell from 52.9% to 41.4% (p < 0.001). CHF was the most frequent primary cardiac diagnosis associated with death, with sepsis representing the most common primary non-cardiac disease (1,226; 25.0%). Overall, the mortality in primary cardiac hospitalizations in PAH was 5.3% (vs. in primary non-cardiac, 6.9%, p < 0.001). On multivariable analysis, a primary cardiac discharge diagnosis remained associated with a decreased risk of death (odds ratio 0.85, p = 0.010). CONCLUSION: Primary cardiac hospitalizations in PAH are common and are associated with decreased mortality compared to admissions for primary non-cardiac diagnoses.

Reduced RVSWI Is Associated With Increased Mortality in Connective Tissue Disease Associated Pulmonary Arterial Hypertension.

Rationale: The prognosis of pulmonary arterial hypertension is poor, especially amongst patients with connective tissue disease related pulmonary arterial hypertension. Right ventricular contractility is known to be decreased in scleroderma related pulmonary arterial hypertension. However, it is not known whether intrinsic right ventricular dysfunction is seen in a general CTD population. Objectives: In this study of a large cohort of patients with pulmonary arterial hypertension with multi-year follow-up, we sought to examine the association of measurements of right ventricular function with survival in connective tissue disease associated pulmonary arterial hypertension. Methods: Clinical characteristics of a deidentified cohort of 845 patients with pulmonary arterial hypertension were compared between patients with and without connective tissue disease. The Kaplan-Meier method was used to examine the survival of patients over more than 4 years. The association between right ventricular stroke work index and mortality was examined in patients with connective tissue disease associated pulmonary arterial hypertension. Measurements and Main Results: Significant differences in the 6-min walk distance, Borg dyspnea index, right ventricular stroke work index, and pulmonary artery pulsatility index were identified between patients with and without connective tissue disease associated pulmonary arterial hypertension. Patients with connective tissue disease had a lower right ventricular stroke work index, which was associated with decreased survival in this group; this association approached significance when adjusting for age and renal function. Conclusions: Right ventricular dysfunction as measured by right ventricular stroke work index is associated with decreased survival in patients with connective tissue disease associated pulmonary arterial hypertension despite similar pulmonary vascular resistance. These findings are suggestive of intrinsic right ventricular function in connective tissue disease associated pulmonary arterial hypertension that has a negative impact on the long-term survival of these individuals.

Hospitalizations with hereditary hemorrhagic telangiectasia and pulmonary hypertension in the United States from 2000 to 2014.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease that causes widespread abnormal vasculature development, resulting in multiple complications including pulmonary hypertension (PH). Despite the potential severity of PH, there is a lack of data on hospitalization characteristics and outcomes in the HHT-PH population. The purpose of this analysis was to describe trends and outcomes of HHT-PH hospitalizations within the National (Nationwide) Inpatient Sample (NIS). METHODS: Adult hospitalizations (age ≥18 years) with a principal or secondary diagnosis of HHT were identified from the 2000-2014 NIS. Records were stratified by a concurrent PH diagnosis. Trends, characteristics, and outcomes of hospitalizations with HHT and PH were analyzed. RESULTS: There were 55,189 adult hospitalizations with HHT from 2000 to 2014, of which 4602 (8.3%) had a concurrent diagnosis of PH. HHT-PH hospitalizations rose steadily from 165 (5.1%) in 2000 to 540 (13.8%) in 2014 (p < 0.001). They were more common in females (vs. HHT without PH, 71.6% vs. 59.2%, p < 0.001) and were associated with a higher comorbidity burden (total 4.0 ±â€¯0.1 vs. 2.4 ±â€¯0.03, p < 0.001). Inpatient mortality was higher in HHT-PH hospitalizations than in HHT without PH (3.5% vs. 1.8%, p < 0.001). On multivariable logistic regression, the diagnosis of PH remained significantly associated with a higher risk of inpatient death (odds ratio 1.71, 95% confidence interval 1.11-2.63, p = 0.015) in HHT hospitalizations. CONCLUSIONS: HHT-PH hospitalizations rose from 2000 to 2014. Notably, HHT patients with a concurrent PH diagnosis were at significantly higher risk of in-hospital mortality.

Statin therapy associated with improved thrombus resolution in patients with deep vein thrombosis.

OBJECTIVE: Statin therapy has been associated with a decreased incidence of venous thromboembolism (VTE) in clinical trials and enhanced thrombus resolution in animal models. The effect of statins on thrombus resolution has not been reported clinically. This study investigates the association of statins with thrombus resolution or improvement in patients with deep venous thrombosis (DVT). METHODS: A retrospective study of the electronic medical records of consecutive adult patients presenting with lower extremity DVT was performed. Patients were divided into two groups based on statin therapy (statin group) or lack thereof (nonstatin group). The two groups were compared with respect to demographics, comorbidities, and risk factors for VTE. Initial as well as all subsequent ultrasound reports were reviewed for each patient to determine extent of DVT and subsequent change in thrombus characteristics. Long-term outcomes examined were mortality, VTE recurrence, and thrombus improvement or resolution on follow-up ultrasound examination. Multivariable analysis was used to determine independent predictors of thrombus resolution or improvement, VTE recurrence, and mortality. RESULTS: A total of 818 patients with DVT were identified (statin group, n = 279 [34%]; nonstatin group, n = 539 [66%]). The patients in the statin group were significantly older (P < .001). Patients on statins were more likely to have risk factors for and manifestations of atherosclerosis and to be on antiplatelet therapy (P < .001), whereas those in the nonstatin group were more likely to have a hypercoagulable disorder (P = .009) or prior DVT (P = .033). There was no significant difference in provoked DVT, extent of DVT, or association with pulmonary embolism (PE), but patients on statins were more likely to have high-risk PE (P = .046). There was no difference in patients receiving anticoagulation, type and duration of anticoagulation, inferior vena cava filter placement, or treatment with lytic therapy. There was no difference in thrombus resolution, mortality, or recurrence of DVT, PE, or VTE between the groups. On multivariable analysis, age, proximal DVT, CAD, and cancer were associated with higher mortality, whereas anticoagulation with coumadin and direct oral anticoagulants and antiplatelet therapy were associated with lower mortality. Statin therapy, antiplatelet therapy, and younger age were associated with thrombus resolution or improvement. CONCLUSIONS: Statin therapy is associated with greater thrombus resolution or improvement in patients with DVT. However, statin therapy in this study was not associated with different clinical outcomes of VTE recurrence or mortality.