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Bronchodilators in Heart Failure Patients With COPD: Is It Time for a Clinical Trial?

Chronic heart failure (HF) and chronic obstructive pulmonary disease (COPD) commonly coexist, and patients with both diseases fare worse than those with either disease alone. Several factors may contribute to worse outcomes, including an increased burden of care related to greater disease complexity, an overlap of symptoms resulting in misapplication of therapy, and the adverse effects of treatment for one disease on the symptoms and outcomes related to the other.

For example, there are conflicting data about the cardiovascular risks of bronchodilators in HF patients who may experience worse outcomes with inhaled beta-2 agonists via arrhythmogenesis, ischemia, and/or attenuation of beta-blocker benefits. In contrast, the long-acting anticholinergic class of bronchodilators has a more reassuring safety profile. Anticholinergic bronchodilators may be the preferred first-line agents for COPD patients with comorbid HF, yet data supporting these recommendations are limited. Therapeutic trials in COPD patients have generally excluded patients with significant HF and vice-versa.

This paper reviews bronchodilator therapy in HF and proposes a randomized trial designed to enroll patients with significant COPD and HF to determine the risks and/or benefits of adding a long-acting beta-2 agonist to patients currently taking a long-acting anticholinergic agent.

Mesenchymal stem cells.

Mesenchymal Stem cells (MSCs) are stromal cells that can be readily harvested from adult bone marrow and adipose tissue, but also umbilical cords. With respect to respiratory disease, the therapeutic potential of these cells lies in their paracrine effects which underlie their ability to enhance tissue regeneration and modulate immune responses.

MSCs have been shown to be effective in a range of murine models of respiratory disease, and there are currently five clinical trials involving the administration of MSCs for respiratory diseases, including COPD and emphysema. This paper summarises the features of MSCs.

Cerebral cortex oxygen delivery and exercise limitation in patients with COPD.

In healthy humans, cerebral oxygen desaturation during exercise affects motor unit recruitment, whilst oxygen supplementation enhances cerebral oxygenation and work capacity. It remains unknown whether in patients with COPD the well documented improvement in exercise tolerance with oxygen supplementation may also be partly due to the increase in cerebral oxygenation.

By near infrared spectroscopy, we measured both frontal cerebral cortex blood flow (CBF) using indocyanine green dye and cerebrovascular oxygen saturation (%StO2) in 12 COPD patients during constant-load exercise to exhaustion at 75% of peak capacity. Subjects exercised breathing air, 100% O2 or normoxic heliox, the latter two in balanced order.Time to exhaustion breathing air was less than for oxygen or heliox (394±35 vs. 670±43 and 637±46 sec, respectively). In each condition, CBF increased from rest to exhaustion. At exhaustion, CBF was higher breathing air and heliox than oxygen (30.9±2.3 and 31.3±3.5 vs. 26.6±3.2 mL·min(-1.)100·g(-1), respectively), compensating lower arterial O2 content (CaO2) in air and heliox, and leading to similar cerebral cortex oxygen delivery (CQO2, air: 5.3±0.4; O2: 5.5±0.6 and heliox: 5.6±1.0 mL O2·min(-1) 100·g(-1)). In contrast, end-exercise %StO2 was greater breathing oxygen compared to air or heliox (67±4 vs. 57±3 and 53±3%, respectively), reflecting CaO2 rather than CQO2.

Prolonged time to exhaustion by oxygen and heliox despite similar CQO2 as in air, lower %StO2 with heliox than oxygen, yet similar endurance time, and similar %StO2 on air and heliox despite greater endurance with heliox, do not support the hypothesis that an improvement in cerebral cortex oxygen availability plays a contributing role in increasing exercise capacity with oxygen or heliox in patients with COPD.

Vitamin D and skeletal muscle strength and endurance in chronic obstructive pulmonary disease.

It is not known whether vitamin D levels make a significant contribution to muscle dysfunction in COPD.

In 104 COPD patients (mean(SD) FEV1 44(22)%predicted) and 100 age and sex-matched controls serum 25(OH)D, 1,25(OH)2D and parathyroid hormone levels were measured and related to quadriceps strength and endurance. In a subset (26 patients, 13 controls) quadriceps biopsy was performed and mRNA expression of myogenic regulatory factors (mrf) and fibre specific myosin heavy chains (MHC) determined.COPD patients were weaker and less physically active than controls. 25(OH)D levels were similar in both groups (48.5(25.5)nmol·l(-1) COPD vs. 55.4(28.3)nmol·l(-1) control, p=0.07) but PTH levels were significantly higher in patients (5.2(2.3)pmol·mL(-1) vs. 4.4(2.0)pmol·l(-1), p=0.01). 1,25(OH)D was significantly correlated with strength in controls but not COPD patients and not with quadriceps endurance assessed using repetitive magnetic stimulation in COPD (n=35) or control (n=35) subjects. In controls but not COPD, muscle biopsy analysis showed a negative relationship between 25(OH)D and MyHCIIa expression (r(2)=0.5, p=0.01) and a positive relationship between mrf4 and MyHCIIa expression (r(2)=0.5, p=0.009), and myf5 and MHCI expression (r(2)=0.72, p=0.004).

In contrast to healthy controls, muscle strength is not associated with vitamin D levels in COPD which may represent vitamin D resistance.

The Relationship between Telomere Length and Mortality in Chronic Obstructive Pulmonary Disease (COPD).

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown.

Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1) and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy "mid-life" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy "mid-life" volunteers (p<.001). Compared to individuals in the 4(th) quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length.

In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.

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