Wassim H. Fares

Thermodilution and Fick cardiac outputs differ: impact on pulmonary hypertension evaluation.

BACKGROUND The relationship between thermodilution and indirect Fick cardiac output determination methods has not been well described. OBJECTIVE To describe the relationship between these two cardiac output determination methods in patients evaluated for pulmonary hypertension and to highlight potential clinical implications. METHODS A retrospective review of charts of all adult patients who underwent a right heart catheterization (RHC) between January 1, 2007 and November 10, 2010, and participated in the pulmonary hypertension program of the pulmonary division at an academic institution was conducted. For validation, the charts of all patients who underwent RHC during the same period within the cardiology division were reviewed. RESULTS A total of 198 patients underwent 213 RHCs, 79 (40%) of whom had pulmonary arterial hypertension, were included. Forty-three per cent of patients had >20% difference between thermodilution and Fick. The average difference (thermodilution - Fick ±SD) was -0.39±2.03 L⁄min (n=213; P=0.006). There was no significant difference in bias or variability between thermodilution and Fick among patients with tricuspid regurgitant jet velocity (TRJ) of <3 m⁄s versus those with TRJ >3 m⁄s (-0.41±2.10 L⁄min versus -0.36±1.93 L⁄min, respectively; P=0.87). In a multivariable analysis, the thermodilution-Fick difference increased with age (P=0.001). DISCUSSION The presence of such discrepancy in 36% of patients evaluated for heart failure and⁄or heart transplant validated the results. In total, 37% of the 1315 procedures (213 performed by pulmonologists and 1102 performed by cardiologists) had a difference of >20% between thermodilution and Fick. CONCLUSION Significant discrepancy exists between thermodilution and indirect Fick methods. This discrepancy potentially impacts pulmonary arterial hypertension prognostication and diagnosis, and is independent of TRJ.

Pulmonary hypertension: diagnostic and therapeutic challenges.

Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic state that can be found in multiple conditions with associated symptoms of dyspnea, decreased exercise tolerance, and progression to right heart failure. The World Health Organization has classified PH into five groups. The first group is pulmonary arterial hypertension (PAH), which can be idiopathic, heritable, due to drugs and toxins, or associated with conditions such as connective tissue diseases, congenital heart disease, portal hypertension, and others. The development of PAH is believed to result from smooth muscle cells and endothelial dysfunction that impairs production of vasodilators, including nitric oxide and prostacyclin. The importance of distinguishing this group from the other groups of PH is that there are PAH-specific drugs that target the molecular pathways that are pathogenic in the vascular derangements, leading to arterial hypertension, which should not be used in the other forms of PH. Other groups of PH include PH due to left heart disease, lung disease, chronic thromboembolic disease, as well as a miscellaneous category. Echocardiography is used to screen for PH and has varying sensitivity and specificity in detecting PH. Additionally, the right heart pressures estimated during echocardiogram often differ from those obtained during confirmatory testing with right heart catheterization. The most challenging PH diagnosis is in a case that does not fit one group of PH, but meets criteria that overlap between several groups. This also makes the treatment challenging because each group of PH is managed differently. This review provides an overview of the five groups of PH and discusses the diagnostic and therapeutic challenges of each.

Pulmonary hypertension in obstructive sleep apnea: is it clinically significant? A critical analysis of the association and pathophysiology.

The development of pulmonary hypertension is a poor prognostic sign in patients with obstructive sleep apnea (OSA) and affects both mortality and quality of life. Although pulmonary hypertension in OSA is traditionally viewed as a result of apneas and intermittent hypoxia during sleep, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressure. Human data show that pulmonary hypertension in the setting of OSA is, in large part, due to left heart dysfunction with either preserved or diminished ejection fraction. Longstanding increased left heart filling pressures eventually lead to pulmonary venous hypertension. The combination of hypoxic pulmonary vasoconstriction and pulmonary venous hypertension with abnormal production of mediators will result in vascular cell proliferation and aberrant vascular remodeling leading to pulmonary hypertension. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest shared mechanisms. The majority of patients with OSA do not receive a diagnosis and are undertreated. Appreciating the high prevalence and understanding the mechanisms of pulmonary hypertension in OSA would lead to better recognition and management of the condition.

Superior vena cava syndrome secondary to saphenous venous graft aneurysm with right atrial fistula.

Mega‐aneurysms of saphenous vein grafts (SVGs) to coronary arteries are rare complications of bypass surgery. We report the development of superior vena cava syndrome secondary to an SVG mega‐aneurysm with concomitant fistulous communication to the right atrium. Successful treatment was achieved by coil embolization and chronic anticoagulation. Catheter Cardiovasc Interv 2003;60:45–47.

Netrin‐1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin‐Induced Pulmonary Fibrosis

Fibrocytes are collagen‐producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)–related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells.

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 thecontributions of the semaphorinreceptor, plexinC1 (PLXNC1), andtheexocytic calcium sensor, synaptotagmin 7 (Syt7), in these processes. Weevaluated the role of PLXNC1 in macrophagemigration by using Boyden chambers and scratch tests, characterized its contribution to experimentally induced lung fibrosis inmice, and defined themechanism for our observations. Our findings reveal that relative to controlparticipants, 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‐β1 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. FASEB J. 30, 4056–4070 (2016). www.fasebj.org

Inhibition of restenosis by hyperbaric oxygen: a novel indication for an old modality.

Hyperbaric oxygen therapy (HOT) is a safe and highly effective modality in the treatment of slow-healing wounds. It has been successfully employed in a variety of clinical conditions including nonhealing diabetic ulcers, chronic osteomyelitis, necrotizing fascitis, compartment syndromes, crush injuries and acute traumatic peripheral ischemia [1,2]. HOT has proven highly effective in the treatment of radiation-induced hemorrhagic cystitis, optic neuritis, decompression sickness, air embolism and CO intoxication [3,4]. Percutaneous coronary interventions (PCIs) invariably create miniature wounds by the disruptive effects of the interventional hardware on the vessel wall, thereby triggering the humoro-cellular responses leading to restenosis. Restenosis accounts for nearly 150,000 PCIs performed annually in this country alone, placing a significant toll on health care resources. It stands to reason to postulate that early healing of these miniature wounds by HOT can decrease restenosis. In an ongoing randomized trial, we embarked to investigate the effect of HOT on restenosis. Our preliminary results have been encouraging [5,6]. The following constitutes our interim comparative findings.

Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is increasingly recognized as a systemic disease driven by alteration in the normal functioning of multiple metabolic pathways affecting all of the major carbon substrates, including amino acids. We found that human pulmonary hypertension patients (WHO Group I, PAH) exhibit systemic and pulmonary-specific alterations in glutamine metabolism, with the diseased pulmonary vasculature taking up significantly more glutamine than that of controls. Using cell culture models and transgenic mice expressing PAH-causing BMPR2 mutations, we found that the pulmonary endothelium in PAH shunts significantly more glutamine carbon into the tricarboxylic acid (TCA) cycle than wild-type endothelium. Increased glutamine metabolism through the TCA cycle is required by the endothelium in PAH to survive, to sustain normal energetics, and to manifest the hyperproliferative phenotype characteristic of disease. The strict requirement for glutamine is driven by loss of sirtuin-3 (SIRT3) activity through covalent modification by reactive products of lipid peroxidation. Using 2-hydroxybenzylamine, a scavenger of reactive lipid peroxidation products, we were able to preserve SIRT3 function, to normalize glutamine metabolism, and to prevent the development of PAH in BMPR2 mutant mice. In PAH, targeting glutamine metabolism and the mechanisms that underlie glutamine-driven metabolic reprogramming represent a viable novel avenue for the development of potentially disease-modifying therapeutics that could be rapidly translated to human studies.

Standard Nonspecific Therapies in the Management of Pulmonary Arterial Hypertension

Recent advances in pulmonary arterial hypertension (PAH) research have created a new era of PAH-specific therapies. Although these therapeutics have revolutionized PAH therapy, their innovation was predated by supportive but nonspecific medical therapies adapted from their use in more common cardiopulmonary diseases. These therapies include oxygen therapy, diuretics, digoxin, anticoagulation, and high-dose calcium channel blockers. Expert opinion continues to support the use of adjunct therapies based on current pathologic understandings of PAH combined with some evidence extrapolated from small studies. This article discusses why these therapies continue to play an important role in the treatment of patients with PAH.

Macitentan for the treatment of pulmonary arterial hypertension.

Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug–drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial.