Beet-ing Muscle Dysfunction and Exercise Intolerance in Pulmonary Hypertension

Indiana University-Purdue University Indianapolis (IUPUI)Background: Pulmonary Hypertension (PH) is a devastating disease characterized by pulmonary arterial remodeling, right ventricular dysfunction and ultimately right heart failure. Increased emphasis has been given to skeletal muscle dysfunction in PH, and to its implication in the severe exercise intolerance that is a hallmark of the condition. In this dissertation, skeletal muscle blood flow was measured via the microsphere technique at rest and during exercise (Aim 1), with an acute dose of dietary nitrate via beetroot juice (BRJ) gavage used to determine if supplementation could improve muscle blood flow and alter energetics (Aim 2). VO2max, voluntary running and grip strength tests were used to determine the effect of disease on performance, and to test for an ergogenic effect of BRJ vs. placebo (PL) in healthy and PH rats (Aim 3). Methods: A prospective, randomized, counterbalanced, placebo-controlled trial was used to examine the aforementioned aims across four groups; PH rats (induced with monocrotaline, MCT, 60mg/kg, s.q., 4 weeks) supplemented with BRJ (MCT BRJ, n=9); PH rats supplemented with placebo (MCT PL, n=9); healthy control rats (vehicle, s.q.) supplemented with BRJ (CON BRJ, n=8); healthy control rats supplemented with placebo (CON PL, n=9). Results: Monocrotaline induced a severe PH phenotype evidenced by increased RV wall thickness, RV hypertrophy, RVSP and reduced cardiac output and stroke volume compared to controls (p=<0.001). MCT rats demonstrated lower muscle blood flow at rest, and more prominently during exercise compared to controls (p=0.007-0.047), regardless of supplementation. MCT rats displayed a greater reliance on anaerobic metabolism, demonstrated by increased blood lactate accumulation (p=<0.001), and this was significantly related to reduced blood flow during exercise (r=-0.5879, p=0.001). BRJ supplementation resulted in increased plasma nitrate and nitrite compared to PL (p=<0.001), but at the skeletal muscle level, only nitrate was increased after BRJ. BRJ did not have a significant effect on blood flow, with no improvement during exercise shown vs. PL. Similarly, BRJ did not significantly improve exercise function in MCT or CON rats. Conclusion: MCT rats demonstrated a reduction in muscle blood flow, with BRJ supplementation not resulting in improved flow or exercise performance

Exercise Intolerance in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is associated with symptoms of dyspnea and fatigue, which contribute to exercise limitation. The origins and significance of dyspnea and fatigue in PAH are not completely understood. This has created uncertainly among healthcare professionals regarding acceptable levels of these symptoms, on exertion, for patients with PAH. Dysfunction of the right ventricle (RV) contributes to functional limitation and mortality in PAH; however, the role of the RV in eliciting dyspnea and fatigue has not been thoroughly examined. This paper explores the contribution of the RV and systemic and peripheral abnormalities to exercise limitation and symptoms in PAH. Further, it explores the relationship between exercise abnormalities and symptoms, the utility of the cardiopulmonary exercise test in identifying RV dysfunction, and offers suggestions for further research

Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency

Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe-4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients

Non-invasive assessment of pulmonary vascular resistance in pulmonary hypertension: Current knowledge and future direction

Pulmonary Hypertension (PHT) is relatively common, dangerous and under-recognised. Pulmonary hypertension is not a diagnosis in itself; it is caused by a number of differing diseases each with different treatments and prognoses. Therefore, timely and accurate recognition of the underlying cause for PHT is essential for appropriate management. This is especially true for patients with Pulmonary Arterial Hypertension (PAH) in the current era of disease-specific drug therapy. Measurement of Pulmonary Vascular Resistance (PVR) helps separate pre-capillary from post-capillary PHT, and is measured with right heart catheterisation (RHC). Echocardiography has been used to derive a number of non-invasive surrogates for PVR, with varying accuracy. Ultimately, the goal of non-invasive assessment of PVR is to separate PHT due to left heart disease from PHT due to increased PVR, to help streamline investigation and subsequent treatment. In this review, we summarise the physiology and pathophysiology of pulmonary blood flow, the various causes of pulmonary hypertension, and non-invasive surrogates for PVR

Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

Age-related changes in the respiratory system

This article summarises the main structural and physiological changes which take place in the lung from young adulthood to senescence. An understanding of these changes helps the clinician to correctly interpret some results of radiology and pulmonary function frequently seen in clinical practice. An appreciation of the altered physiology and the consequent reduction in pulmonary reserve should alert the physician to the need for a more critical evaluation of the various respiratory parameters measured during illness in an older patient. Rhythmic breathing occurs virtually continuously over a lifetime and the alveolar gas-exchanging surface is brought into contact with more than 270 million litres of air, which may contain harmful particulate matter and noxious gas elements. Thus to separate changes in the respiratory system caused by ageing itself from those caused by environmental or work-related factors is extremely difficult and sometimes impossible. Chronic obstructive pulmonary disease (COPD) is possibly the most important disease entity related to age and environment. Epidemiological studies show that the prevalence of COPD is increasing. In the 1990’s prognostic models of COPD were developed. These have shown that age, ventilatory function, gender and smoking were the major determinants for the development of COPD. Other important factors were outdoor air pollution and occupation.peer-reviewe

Skeletal muscle, exercise and activity in pulmonary hypertension

MD ThesisPulmonary Arterial hypertension (PAH) is a rare and progressive condition presenting with exercise intolerance, leading to right ventricle (RV) failure and death. There has been significant progress in understanding the basic pathophysiology leading to the development of a number of targeted therapies, resulting in improved prognosis. Despite this, patients remain limited in performing exertional activities with a poorer quality of life. Recent research has focused on PAH being a multi-systemic disease with skeletal muscle dysfunction contributing to exercise intolerance. There needs to be greater understanding of the physiological and behavioural mechanisms that limit daily functional capabilities in PAH patients. The aims of the thesis were to study the role of skeletal muscle mitochondrial function, the limitations in central and peripheral haemodynamics on maximum exercise, and develop a greater understanding of whether habitual daily physical activity levels are improved by current pharmaceutical treatments. Using 31Phosphorous-magnetic resonance spectroscopy (31P-MRS), oxygen delivery as opposed to impaired mitochondrial function would explain the abnormal skeletal muscle bioenergetics observed. This is further supported by analysing skeletal muscle biopsy samples demonstrating that mitochondrial protein expression and function was normal, therefore not contributing to impaired exercise capacity. Using continuous non-invasive cardiac output, chronotropic incompetence and reduced peripheral oxygen extraction are the predominant mechanisms leading to impaired peak oxygen consumption. Finally, in a pilot study targeted-therapies failed to change habitual daily physical activity and fatigue levels in PAH patients despite a significant observed change in submaximal exercise capacity. In conclusion, a number of physiological mechanisms that impair exercise capacity and habitual physical activity in PAH are beyond the currently available targeted therapies. Further research is needed into how best to improve exercise capacity, fatigue and activity levels that will directly lead to improvement in quality of life for PAH patients

The molecular genetics and cellular mechanisms underlying pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards

A study of clinical and physiological relations of daily physical activity in precapillary pulmonary hypertension.

Daily physical activity is reduced in precapillary pulmonary hypertension (PH) but the underlying mechanisms are inadequately explored. We sought to investigate clinical and physiological relations of daily physical activity and profile differences between less and more active patients with precapillary PH. A prospective, cross-sectional study of 20 patients with precapillary PH who undertook a) a comprehensive clinical assessment, b) a preliminary treadmill test, c) 7-day monitoring of daily walking intensity with triaxial accelerometry and d) a personalized treadmill test corresponding to the individual patient mean daily walking intensity with real-time physiological measurements. Significant clinical correlations with individual patient mean walking intensity (1.71±0.27 m/s2) were observed for log N-terminal pro-brain natriuretic peptide (log-NTproBNP: r=-.75, p=<.001), age (r=-.70, p=.001), transfer factor for carbon monoxide %predicted (r=.51, p=0.022) and 6-minute walk distance (r=.50, p=.026). Significant physiological correlations were obtained for heart rate reserve (r=.68, p=.001), quadriceps tissue oxygenation index (Q-StO2: r=.58, p=.008), change in Q-StO2 from rest (r=.60, p=.006) and ventilatory equivalent for oxygen uptake (r=-.56, p=.013). Stepwise multiple regression analyses retained log-NTproBNP (R2=0.55), heart rate reserve (R2=0.44) and Q-StO (R2=0.13) accounting for a significant variance in individual walking intensity. Less active patients had greater physical activity-induced cardiopulmonary impairment, worse quadriceps oxygenation profile and compromised health-related quality of life compared to more active patients. These preliminary findings suggest a significant relation between right ventricular and peripheral muscle oxygenation status and reduced daily physical activity in precapillary PH. Further research is warranted to unravel the physiological determinants, establish clinical predictors, and identify beneficial interventions

Age-associated Arterial Remodelling and Cardiovascular Diseases

Arterial remodelling is a major risk factor for a variety of age-related diseases and represents a potential target for therapeutic development. During ageing, the structural, mechanical and functional changes of arteries predispose individuals to the development of diseases related to vascular abnormalities in vital organs such as the brain, heart, eye and kidney. For example, aortic stiffness increases nonlinearly with advancing age – a few percent prior to 50 years of age but over 70% after 70 years of age. The elevated stiffness in large elastic arteries leads to increased transmission of high pressure to downstream smaller blood vessels, in turn affecting the microcirculation and end-organ functions. Meanwhile, the augmented remodelling of small arteries accelerates central arterial stiffening. This chapter is to provide an overview of age-associated changes in the arterial wall and their contributions to both central and peripheral vascular abnormalities associated with ageing. Therapeutics that specially target the different aspects of arterial remodelling are expected to be more effective than the traditional medications, particularly for the treatment and management of vascular ageing-related diseases.published_or_final_versio