Exertional and nocturnal periodic breathing after successful cardiac transplantation. A case report.

We present a case report of a heart failure patient who underwent cardiopulmonary exercise testing and sleep screening 12 months before and after heart transplantation (HTx). Severe Cheyne-Stokes respiration (CSR) with central sleep apnoea (CSA) was identified either before and after HTx, while periodic breathing during exercise vanished. We suggest that optimization of hemodynamics and medical therapy (low dose of diuretic) did not withdraw the central mechanisms underlying the diathesis for CSR-CSA. While periodic breathing during exercise reversal may support a closer link with an exertional central hemodynamic. This observation indirectly neglects the possible unifying mechanistic background of CSR and periodic breathing, during exercise, in this setting

Cardiovascular disease patients and predictors of length of stay of residential of cardiac rehabilitation. A specific rehabilitation is mandatory in very old patients?

As more adults are living into old age, they are predisposed to cardiovascular disease (CVD) and the demand for cardiac rehabilitation is increasing. We aimed to verify predictors of length of stay (LOS) in young (Y) vs older (O) vs very old (VO) CVD patients, admitted to residential cardiac rehabilitation. Patients' demographic and clinical characteristics at admission, as well as Barthel index (BI), Cumulative Illness Rating Scale (CIRS), comorbidity severity/complexity, NYHA classification, left ventricular ejection fraction (LVEF), physical activity level were compared in Y (≤65 years) vs O (between >65 and <76 years) vs VO patients (with an age of ≥76 years) against LOS. In 5,070 consecutively CVD patients were included; they were 1392 Y (38%) 1944 O (35%) 1334 VO patients (27%) and LOS duration was 16±7, 19±9 and 22±10 days, respectively (p<0.0001). In Y, LOS was linked to BI (p=0.000) and to LVEF (p=0.000) at multivariable analysis with area under ROC curve of 0.82, whereas in O, LOS was associated to gender (p=0.013) CIRS severity (p=0.000), BI (p=0.000), LVEF (p=0.000), and in those VO to gender (p=0.004), BI (p=0.000) and medical infusion (p=0.000) at multivariable with ROC curve of 0.83 and 0.74, respectively. In very old patients, a prolonged LOS is related to extra-cardiac conditions. Therefore, we promote a specific cardiac rehabilitation for these patients

Phospho-p38 MAPK expression in COPD bronchi and in oxidative and inflammatory challenged bronchial epithelium

The role of MAPK kinases in inducing the inflammatory response in the airways of chronic obstructive pulmonary diseases (COPD) patients is incompletely studied. Objectives: To investigate the expression of activated MAPK kinases in bronchial biopsies of COPD patients and the MAPK kinase bronchial epithelial response to oxidative and inflammatory stimuli related to COPD. Expression of phospho(p)-p38, p-JNK1 and p-ERK1/2 was measured in the bronchial mucosa using immunohistochemistry in patients with mild/moderate (n=17), severe/very severe (n=16) stable COPD, control smokers (n=16), control non smokers (n=9) and in a group with mild asthma (n=9). 16HBE cells, challenged with oxidative and inflammatory stimuli, were also studied for IL-8 and MAPK kinases mRNA production. P-p38 was the most expressed MAPK kinase in the bronchial mucosa of all subjects. No significant differences were observed for immune-expression of p-p38, p-JNK and p-ERK1/2 between COPD and control subjects. 16HBE cells treated with H2O2, cytomix (TNFα+IL- 1β+IFNγ) and Lipopolysaccharide (LPS) up-regulated IL-8 mRNA production at 1h or 2h after treatments. P38α mRNA was significantly increased after H2O2 and LPS. JNK1 and ERK1 mRNA were not significantly increased after H2O2, cytomix or LPS treatments. Blocking p38α activity IL-8 mRNA production was not changed at 1h, 2h and 4h after H2O2 or LPS challenge. P-p38 immune-positivity is prevalent in the bronchial mucosa of COPD and asthmatic patients and p38 mRNA is increased after bronchial epithelial challenges suggesting a relevant role for this MAPK kinase in the induction of bronchial inflammation in COPD and asthma

Convergent Sets of Data from In Vivo and In Vitro Methods Point to an Active Role of Hsp60 in Chronic Obstructive Pulmonary Disease Pathogenesis

BACKGROUND: It is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses. METHODS AND RESULTS: Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE) caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H\u2082O\u2082. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H\u2082O\u2082 treatment in the absence of cell death. CONCLUSIONS: This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COP

Indexes of Angiogenic Activation in Myocardial Samples of Patients with Advanced Chronic Heart Failure

Background and objectives: Ischemic and idiopathic heart failure are characterized by reactive cardiac fibrosis and impaired vasculogenesis involving pro-angiogenic factors such as angiogenin, angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2), as demonstrated in experimental models of heart failure. However, differences in the molecular pathways between these cardiomyopathies are still unclear. In this short communication, we evaluate and compare the expression of pro-angiogenic molecules in the heart tissue of patients with advanced chronic heart failure (CHF) of ischemic vs. nonischemic etiology. Materials and Methods: We obtained heart tissue at transplantation from left ventricular walls of 16 explanted native hearts affected by either ischemic (ICM) or nonischemic dilated cardiomyopathy (NIDCM). Tissue samples were examined using immunohistochemistry for angiogenic molecules. Results: We found immunopositivity (I-pos) for angiopoietin-1 mainly in the cardiomyocytes, while we observed I-pos for Ang-2 and Tie-2 receptor mainly in endothelial cells. Expression of Procollagen-I (PICP), angiogenin, Ang-1, and Tie-2 receptor was similar in ICM and NIDCM. In contrast, endothelial immunopositivity for Ang-2 was higher in ICM samples than NIDCM (p = 0.03). Conclusions: In our series of CHF heart samples, distribution of Ang-1 and angiogenin was higher in cardiomyocytes while that of Ang-2 was higher in endothelial cells; moreover, Ang-2 expression was higher in ICS than NIDCM. Despite the small series examined, these findings suggest different patterns of angiogenic stimulation in ICM and NIDCM, or at least a more altered endothelial integrity in ICD. Our data may contribute to a better understanding of the angiogenesis signaling pathways in CHF. Further studies should investigate differences in the biochemical processes leading to heart failure

Impact of Galectin-3 Circulating Levels on Frailty in Elderly Patients with Systolic Heart Failure

Background: Heart Failure (HF), a leading cause of morbidity and mortality, represents a relevant trigger for the development of frailty in the elderly. Inflammation has been reported to play an important role in HF and frailty pathophysiology. Galectin-3 (Gal-3), whose levels increase with aging, exerts a relevant activity in the processes of cardiac inflammation and fibrosis. The aim of the present study was to investigate the potential of Galectin-3 to serve as a biomarker of frailty in HF patients. Methods: 128 consecutive patients aged 65 and older with the diagnosis of systolic HF underwent a frailty assessment and blood sample collection for serum Gal-3 detection. A multivariable regression analysis and decision curve analysis (DCA) were used to identify significant predictors of frailty. Results: Frailty was present in 42.2% of patients. Age: Odds Ratio (OR) = 3.29; 95% Confidence Interval CI (CI) = 1.03-10.55, Cumulative Illness Rating Scale Comorbidity Index (CIRS-CI): OR = 1.85; 95% CI = 1.03-3.32, C-Reactive phase Protein (CRP) OR = 3.73; 95% CI = 1.24-11.22, N-terminal-pro-Brain Natriuretic Peptide (NT-proBNP): OR = 2.39; 95% CI = 1.21-4.72 and Gal-3: OR = 5.64; 95% CI = 1.97-16.22 resulted in being significantly and independently associated with frailty. The DCA demonstrated that the addition of Gal-3 in the prognostic model resulted in an improved clinical 'net' benefit. Conclusions: Circulating levels of Gal-3 are independently associated with frailty in elderly patients with systolic HF

Extracorporeal Shock Waves Increase Markers of Cellular Proliferation in Bronchial Epithelium and in Primary Bronchial Fibroblasts of COPD Patients

Chronic obstructive pulmonary disease (COPD) is due to structural changes and narrowing of small airways and parenchymal destruction (loss of the alveolar attachment as a result of pulmonary emphysema), which all lead to airflow limitation. Extracorporeal shock waves (ESW) increase cell proliferation and differentiation of connective tissue fibroblasts. To date no studies are available on ESW treatment of human bronchial fibroblasts and epithelial cells from COPD and control subjects. We obtained primary bronchial fibroblasts from bronchial biopsies of 3 patients with mild/moderate COPD and 3 control smokers with normal lung function. 16HBE cells were also studied. Cells were treated with a piezoelectric shock wave generator at low energy (0.3 mJ/mm2, 500 pulses). After treatment, viability was evaluated and cells were recultured and followed up for 4, 24, 48, and 72 h. Cell growth (WST-1 test) was assessed, and proliferation markers were analyzed by qRT-PCR in cell lysates and by ELISA tests in cell supernatants and cell lysates. After ESW treatment, we observed a significant increase of cell proliferation in all cell types. C-Kit (CD117) mRNA was significantly increased in 16HBE cells at 4 h. Protein levels were significantly increased for c-Kit (CD117) at 4 h in 16HBE ( &lt; 0.0001) and at 24 h in COPD-fibroblasts ( = 0.037); for PCNA at 4 h in 16HBE ( = 0.046); for Thy1 (CD90) at 24 and 72 h in CS-fibroblasts ( = 0.031 and  = 0.041); for TGFβ1 at 72 h in CS-fibroblasts ( = 0.038); for procollagen-1 at 4 h in COPD-fibroblasts ( = 0.020); and for NF-κB-p65 at 4 and 24 h in 16HBE ( = 0.015 and  = 0.0002). In the peripheral lung tissue of a representative COPD patient, alveolar type II epithelial cells (TTF‐1+) coexpressing c-Kit (CD117) and PCNA were occasionally observed. These data show an increase of cell proliferation induced by a low dosage of extracorporeal shock waves in 16HBE cells and primary bronchial fibroblasts of COPD and control smoking subjects

Upregulation of Notch Signaling and Cell-Differentiation Inhibitory Transcription Factors in Stable Chronic Obstructive Pulmonary Disease Patients

Notch signaling is involved in the prevention of cell differentiation and cell fate in various organs, including the lungs. We aimed to determine the transcriptomic and protein expression of Notch receptors, their ligands, and related transcription factors in stable COPD. The expression and localization of Notch receptors, their ligands, and related transcription factors were measured in bronchial biopsies of individuals with stable mild/moderate (MCOPD) (n = 18) or severe/very severe (SCOPD) (n = 16) COPD, control smokers (CSs) (n = 13), and control nonsmokers (CNSs) (n = 11), and in the lung parenchyma of those with MCOPD (n = 13), CSs (n = 10), and CNSs (n = 10) using immunohistochemistry, ELISA tests, and transcriptome analyses. In the bronchial biopsies, Notch4 and HES7 significantly increased in the lamina propria of those with SCOPD compared to those with MCOPD, CSs, and CNSs. In the peripheral lung bronchiolar epithelium, Notch1 significantly increased in those with MCOPD and CSs compared to CNSs. ELISA tests of lung parenchyma homogenates showed significantly increased Notch2 in those with MCOPD compared to CSs and CNSs. Transcriptomic data in lung parenchyma showed increased DLL4 and HES1 mRNA levels in those with MCOPD and CSs compared to CNSs. These data show the increased expression of the Notch pathway in the lungs of those with stable COPD. These alterations may play a role in impairing the regenerative–reparative responses of diseased bronchioles and lung parenchyma

Bone Morphogenic Proteins and Their Antagonists in the Lower Airways of Stable COPD Patients

Background: Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs. Objective: To determine transcriptomic and protein expression of BMPs and their antagonists in stable COPD. Methods: We measured the expression and localization of BMPs and some relevant antagonists in bronchial biopsies of stable mild/moderate COPD (MCOPD) (n = 18), severe/very severe COPD (SCOPD) (n = 16), control smokers (CS) (n = 13), and control non-smokers (CNS) (n = 11), and in lung parenchyma of MCOPD (n = 9), CS (n = 11), and CNS (n = 9) using immunohistochemistry and transcriptome analysis, in vitro after the stimulation of the 16HBE cells. Results: In bronchial biopsies, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium and lamina propria of COPD patients. BMP4 expression was decreased in the bronchial epithelium of SCOPD and MCOPD compared to CNS. Lung transcriptomic data showed non-significant changes between groups. CRIM1 and chordin were significantly decreased in the alveolar macrophages and alveolar septa in COPD patients. External 16HBE treatment with BMP4 protein reduced the bronchial epithelial cell proliferation. Conclusions: These data show an imbalance between BMP proteins and their antagonists in the lungs of stable COPD. This imbalance may play a role in the remodeling of the airways, altering the regenerative-reparative responses of the diseased bronchioles and lung parenchyma