Ventilatory and cardiocirculatory exercise profiles in COPD: the role of pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a well-recognized complication of COPD. The impact of PH on exercise tolerance is largely unknown. We evaluated and compared the circulatory and ventilatory profiles during exercise in patients with COPD without PH, with moderate PH, and with severe PH. METHODS: Forty-seven patients, GOLD (Global Initiative for Chronic Obstructive Lung Disease)stages II to IV, underwent cardiopulmonary exercise testing and right-sided heart catheterization at rest and during exercise. Patients were divided into three groups based on mean pulmonary artery pressure (mPAP) at rest: no PH (mPAP, < 25 mm Hg), moderate PH (mPAP, 25-39 mm Hg),and severe PH (mPAP, ≥ 40 mm Hg). Mixed venous oxygen saturation (S VO 2 ) was used for evaluating the circulatory reserve. Pa CO 2 and the calculated breathing reserve were used for evaluation of the ventilatory reserve. RESULTS: Patients without PH (n = 24) had an end-exercise S VO 2 of 48%± 9%, an increasing Pa CO 2 with exercise, and a breathing reserve of 22% ± 20%. Patients with moderate PH (n = 14) had an exercise S VO 2 of 40% ± 8%, an increasing Pa CO 2 , and a breathing reserve of 26% ± 15%. Patients with severe PH (n =9) had a significantly lower end-exercise S VO 2 (30% ± 6%), a breathing reserve of 37% ± 11%, and an absence of Pa CO 2 accumulation. CONCLUSION: Patients with severe PH showed an exhausted circulatory reserve at the end of exercise.A profile of circulatory reserve in combination with ventilatory impairments was found inpatients with COPD and moderate or no PH. The results suggest that pulmonary vasodilation might only improve exercise tolerance in patients with COPD and severe PH.

Acute effects of sildenafil on exercise pulmonary hemodynamics and capacity in patients with COPD.

BACKGROUND: We investigated in chronic obstructive pulmonary disease (COPD) patients whether a single dose of sildenafil can attenuate the exercise-induced increase in pulmonary artery pressure, thereby allowing augmentation of stroke volume (SV), and improving maximal exercise capacity. METHODS: Eighteen COPD patients (GOLD II-IV) underwent right heart catheterization at rest and submaximal exercise. Mean pulmonary artery pressure (mPpa) and cardiac output (CO) were assessed. Resting and exercise measurements were repeated 60 min after oral intake of 50mg sildenafil. Also, on different days, patients performed two maximal exercise tests (CPET) randomly, 1h after placebo and after 50mg sildenafil. RESULTS: Five COPD patients had pulmonary hypertension (PH) at rest (mPpa >25 mmHg) and six developed PH during exercise (mPpa >30 mmHg). In all patients, mPpa increased from rest to submaximal exercise (23+/-10-35+/-14 mmHg). After sildenafil mPpa at rest was 20+/-10 mmHg, in exercise mPpa was increased less to 30+/-14 mmHg (p<0.01). The reduced augmentation in mPpa was not accompanied by an increased SV and CO. In COPD patients with PH the percentage increase in mPpa to submaximal exercise was 68% before, and 51% after oral intake of sildenafil (p=0.07). In COPD without PH, these values were 46% and 41% (ns), respectively. Maximal exercise capacity and CPET characteristics were unchanged after sildenafil. CONCLUSION: Regardless of mPpa at rest, sildenafil attenuates the increase in mPpa during submaximal exercise in COPD. This attenuated increase is neither accompanied by enhanced SV and CO, nor by improved maximal exercise capacity.

Prolonged engraftment of human hepatocytes in mice transgenic for the deleted form of human hepatocyte growth factor.

AIM: Small animal models chimeric for human hepatocytes have provided valuable insights into the biology of hepatotropic viral infection and provided a platform for the study of therapeutic agents. Existing models of human hepatocyte transplantation are limited by phenotypic fragility and impaired immunity. We hypothesized that mice transgenic for human hepatocyte growth factor (HGF), a potent human hepatocyte mitogen, would engraft human hepatocytes in the absence of immunodeficiency. METHODS: A plasmid construct containing the 2.3 kb coding region of the 723 amino acid isoform of HGF cDNA under the transcriptional control of the mouse albumin promoter/enhancer was used to generate transgenic mice. Cryopreserved human hepatocytes were transplanted into nine transgenic and six non-transgenic mice. Engraftment of human hepatocytes was followed for a period of 12 weeks by immunoblotting for human albumin in mouse serum samples. RESULTS: In six out of the nine transgenic mice, abundance of human albumin, following an initial decline, increased andpeaked at > 70 days post transplantation, demonstrating sustained engraftment of transplanted human hepatocytes. In all the non-transgenic mice, post-transplant human albumin levels declined sequentially without evidence of sustained engraftment. Immunostaining of mouse liver sections indicated the presence of human hepatocytes adjacent to clusters of non-staining murine hepatocytes. CONCLUSION: These results demonstrate that sustained engraftment of human hepatocytes in mice is facilitated by expression of the human dHGF transgene. Human hepatocyte engraftment in this model has been achieved on an immunocompetent strain background and merits further study as a candidate for the study of hepatotropic viral infections.