Nathan Hatton

Right Ventricular Adaptation and Failure in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patients functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.

The right ventricle under pressure: evaluating the adaptive and maladaptive changes in the right ventricle in pulmonary arterial hypertension using echocardiography (2013 Grover Conference series)

The importance of the right ventricle (RV) in pulmonary arterial hypertension (PAH) has been gaining increased recognition. This has included a reconceptualization of the RV as part of an RV–pulmonary circulation interrelated unit and the observation that RV function is a major determinant of prognosis in PAH. Noninvasive imaging of RV size and function is critical to the longitudinal management of patients with PAH, and continued understanding of the pathophysiology of pulmonary vascular disease relies on the response of the RV to pulmonary vascular remodeling. Echocardiography, in particular the newer echocardiographic measurements and techniques, allows easy, readily accessible means to assess and follow RV size and function.

Low-dose naltrexone for pruritus in systemic sclerosis.

Pruritus is a common symptom in systemic sclerosis (SSc), an autoimmune disease which causes fibrosis and vasculopathy in skin, lung, and gastrointestinal tract (GIT). Unfortunately, pruritus has limited treatment options in this disease. Pilot trials of low-dose naltrexone hydrochloride (LDN) for pruritus, pain, and quality of life (QOL) in other GIT diseases have been successful. In this case series we report three patients that had significant improvement in pruritus and total GIT symptoms as measured by the 10-point faces scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire. This small case series suggests LDN may be an effective, highly tolerable, and inexpensive treatment for pruritus and GIT symptoms in SSc.

Transforming growth factor signalling: A common pathway in pulmonary arterial hypertension and systemic sclerosis

Pulmonary arterial hypertension (PAH) is a clinical condition characterised by the presence of precapillary pulmonary hypertension (PH). Included within the subcategorisation of PAH are heritable (HPAH) and PAH associated various conditions (APAH) including systemic sclerosis (SSc). The pathogenesis of HPAH and SSc has been linked to both a genetic predisposition and epigenetic factors. TGF‐β superfamily signalling has also been implicated in the development of these conditions. In this review, we discuss the role of genetic predisposition, epigenetic factors along with dysregulation in TGF‐β superfamily signalling in the pathogenesis of PAH and SSc.

The Vascular Microenvironment and Systemic Sclerosis

The role of the vascular microenvironment in the pathogenesis Systemic Sclerosis (SSc) is appreciated clinically as Raynauds syndrome with capillary nail bed change. This manifestation of vasculopathy is used diagnostically in both limited and diffuse cutaneous subsets of SSc, and is thought to precede fibrosis. The degree of subsequent fibrosis may also be determined by the vascular microenvironment. This paper describes why the vascular microenvironment might determine the degree of end-organ damage that occurs in SSc, with a focus on vascular cell senescence, endothelial progenitor cells (EPC) including multipotential mesenchymal stem cells (MSC), pericytes, and angiogenic monocytes. An explanation of the role of EPC, pericytes, and angiogenic monocytes is important to an understanding of SSc pathogenesis. An evolving understanding of the vascular microenvironment in SSc may allow directed treatment.

Pulmonary arterial hypertension in primary amyloidosis

Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition.

Phanerochaete chrysosporium and granulomatous lung disease in a mulch gardener.

A 50‐year‐old woman who gardens regularly with rotting bark mulch presented with exertional dyspnea, diffusion impairment, and radiographic abnormalities (centrilobular nodules, tree‐in‐bud and ground glass opacities, calcified mediastinal and hilar lymph nodes) on a computed tomogram. Moderate lymphocytosis was noted on bronchoalveolar lavage. Surgical biopsy of her lung revealed granulomatous changes, and biopsies grew Phanerochaete chrysosporium, a fungus that causes white rot in tree bark. She was treated with voriconazole and instructed to avoid gardening, which led to radiographic and symptomatic improvement. She had recurrence of symptoms when she started doing yard work again. P. chrysosporium has been demonstrated to cause hypersensitivity pneumonitis in animal models. This case is the first documented report of P. chrysosporium associated with granulomatous lung disease in a human.

The Complicated Question of Anticoagulation in Pulmonary Arterial Hypertension: Time to Get Some Simple Answers

According to Dr Seuss, “Sometimes the questions are complicated and the answers are simple.” However, when practitioners are asked if anticoagulation is beneficial in pulmonary arterial hypertension (PAH), it is the question that is simple and the answer that is quite complicated. The histology of PAH is characterized by plexiform lesions, vasoconstriction, medial hypertrophy, intimal hyperplasia, perivascular inflammation, and thrombotic lesions within the pulmonary vasculature. The aetiology of these pathologic lesions remains unclear but has been associated with drug exposures, genetic mutations, and other systemic diseases including cirrhosis, HIV, and collagen vascular diseases. Despite the diverse risk factors for the development of PAH, the therapeutic options currently available have focused on pulmonary vasodilation and improvement in right ventricular function. Randomized controlled trials (RCTs) of antiinflammatory and antiproliferative agents have failed to show clinical benefit or decrease the vascular remodelling seen in PAH. Although pulmonary vasodilators have contributed to an improved prognosis in PAH, 1-year mortality rates remain considerable at 7%-17%. Additionally, mortality differs between phenotypes of PAH, and most particularly is worse in scleroderma-associated PAH. In this setting, efforts to define optimum pharmacotherapy in PAH and individualize therapy based on clinical phenotype are important tasks facing PAH providers. One potential therapeutic approach that has remained somewhat controversial is the use of warfarin and anticoagulation in PAH. In 1992, Rich and colleagues found survival was significantly better in patients given anticoagulation when concurrent therapies with calcium channel blockers were examined. Although these patients were not randomized nor was anticoagulation the primary intervention,

Right-to-left ventricular end diastolic diameter ratio in severe sepsis and septic shock

Purpose: The ratio of right ventricular end‐diastolic diameter (EDD) to left ventricular EDD (RV/LV) is a measure predictive of right ventricular failure. We hypothesized that an increase in RV/LV would be associated with poor prognosis in severe sepsis and septic shock. Materials and methods: This is a retrospective chart review of patients with severe sepsis and septic shock admitted to a medical intensive care unit (ICU) at a single tertiary care hospital. Patients were identified by ICD‐9 codes: 995.92 for severe sepsis and 785.52 for septic shock; and had to have an echocardiogram within 48 h of ICU admission. Increased RV/LV was defined as RV/LV ≥ 0.9. Left and right‐sided chamber dimensions were measured according to American Society of Echocardiography guidelines. Results: We included 146 consecutive ICU patients admitted with septic shock (72) or severe sepsis (74). There was no significant difference in ICU mortality in patients with RV/LV ≥ 0.9 versus RV/LV < 0.9 (p = .49). Conclusions: An increased RV/LV does not predict mortality in severe sepsis or septic shock.

The Approach to the Patient With Chronic Dyspnea of Unclear Etiology

Dyspnea is defined by the American Thoracic Society as a “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.”1 It is a common nonspecific symptom in patients presenting to both primary care and subspecialty medical providers. Dyspnea can be the presenting complaint for a large variety of disease processes and as a result, patients see several specialists for upwards of 2 years prior to formal diagnoses (Table 1).2–4 For example, nearly 90% of people with pulmonary arterial hypertension (PAH) present with dyspnea on exertion,5 but distinguishing between dyspnea caused by PAH from dyspnea caused by other cardiac or pulmonary disease—or a whole host of other conditions—is challenging. In this review, we will discuss the diagnostic approach to patients presenting with chronic dyspnea of inexact etiology.