Christos Kapelios

Hormonal imbalance in relation to exercise intolerance and ventilatory inefficiency in chronic heart failure

BACKGROUND Skeletal muscle wasting is associated with altered catabolic/anabolic balance and poor prognosis in patients with chronic heart failure (CHF). This study evaluated catabolic and anabolic abnormalities in relation to disease severity in CHF patients. METHODS Forty-two stable CHF patients (34 men; aged 56±12 years, body mass index, 27±5 kg/m2) receiving optimal medical treatment underwent incremental symptom-limited cardiopulmonary exercise testing on a cycle ergometer. Blood samples were drawn within 10 days to determine serum cortisol, plasma adrenocorticotropin (ACTH), and serum dehydroepiandrosterone sulfate, insulin-like growth factor 1, growth hormone, and total testosterone in men. RESULTS Patients with higher cortisol levels presented with impaired peak oxygen uptake (Vo2 peak: 18.3±3.9 vs. 14.2±3.7 ml/kg/min, p<0.01), ventilatory (Ve) response to exercise (Ve/carbon dioxide output [Vco2] slope: 36±6 vs 30±5, p<0.01), and chronotropic reserve ([peak heart rate [HR]--resting HR/220--age--resting HR]×100%: 40±19 vs. 58±18, p=0.01) compared with those with lower serum cortisol. Cortisol was inversely correlated with Vo2 peak, (r = -0.57; p<0.01) and was correlated with Ve/Vco2 slope (r = 0.47; p<0.01) and chronotropic reserve (r = 0.44; p = 0.017). In multivariate regression analysis, cortisol was an independent predictor of Vo2peak (R2 = 0.365, F = 12.5, SE = 3.4; p≤0.001) and Ve/Vco2 slope (R2 = 0.154; F = 8.5; SE = 5.96; p = 0.006), after accounting for age, body mass index, sex, CHF etiology, creatinine, left ventricular ejection fraction, and ACTH in all patients. In men, cortisol and dehydroepiandrosterone levels were both independent predictors of Vo2peak (R2 = 0.595, F = 24.53, SE = 2.76; p<0.001) after accounting also for all measured hormones, whereas cortisol remained the only independent predictor of Ve/Vco2 slope (R2 = 0.133; F = 6.1; SE = 6.2; p = 0.02). CONCLUSIONS Enhanced catabolic status is significantly associated with exercise intolerance, ventilatory inefficiency, and chronotropic incompetence in CHF patients, suggesting a significant contributing mechanism to their limited functional status.

Bone Metabolism in Chronic Heart Failure

Purpose: Chronic Heart Failure (HF) is complicated by bone loss and osteoporosis, which have been linked to hyperparathyroidism. We studied the bone metabolism and possible role of cytokines in patients suffering from HF. Methods and results: We measured bone alkaline phosphatase (BALP), C-telopeptides of type I collagen (β-CTx) and Interleukin-(IL) 6 in 60 men, 56 ± 11 years of age, suffering from chronic HF, and in 13 age-matched men free from HF. We also measured total body and femoral bone densitometry and parathyroid hormone (PTH). The β-CTx concentrations were significantly higher in men with than in men without HF. The concentrations of BALP (12.4 ± 4.9 vs. 9.9 ± 3 μg/l; P=0.03) and β-CTx (0.67 ± 0.35 vs. 0.33 ± 0.21 ng/ml; P<0.001) were significantly higher in patients in New York Heart Association (NYHA) functional classes III or IV than in patients in classes I or II. Moderately strong correlations were observed between β-CTx, BALP, PTH and bone densitometry measurements. Positive correlations were observed between NYHA functional classes and a) mean PTH (r2=0.19; P<0.001) and b) mean β-CTx (r2=0.30; P<0.001) concentrations. Moreover, increasing serum β-CTx and BALP concentrations were correlated with measurements consistent with decreasing bone mass and increasing severity of HF. IL-6 was also correlated with β-CTx, BALP and PTH, though not with measurements of bone density. Increased serum concentrations of IL-6 were correlated with the severity of HF. β-CTx was a strong predictor of adverse clinical events (hazard ratio 6.32; 95% confidence interval 1.8-22.5; P=0.005), including after controlling for other prognostic markers of chronic HF severity and measurements of bone densitometry. Conclusion: Chronic HF, particularly at advanced stages, was associated with an acceleration of bone turnover and uncoupling of bone formation and resorption. These changes in bone metabolism, among others, could be due to secondary hyperparathyroidism and the chronic inflammatory state associated with chronic HF. The increased osteoclastic activity observed in chronic HF was associated with a poor prognosis.

EFFECTS OF A NOVEL IMPLANTABLE COUNTERPULSATION ASSIST DEVICE ON LEFT VENTRICULAR MECHANOENERGETICS: COMPARISON WITH THE INTRA-AORTIC BALLOON PUMP IN A PORCINE MODEL OF ACUTE HEART FAILURE

We have developed a novel implantable counterpulsation left ventricular (LV) assist device, the Pressure-Unloading Left Ventricular Assist Device (PULVAD). We compared the effects of PULVAD support on LV mechanoenergetics to those induced by the intra-aortic balloon pump (IABP) in a porcine model of

EARLY AND LATE CARDIOPROTECTIVE EFFECTS OF INTRACORONARY ADMINISTRATION OF 4-CHLORODIAZEPAM IN A RAT MODEL OF ISCHEMIA/REPERFUSION

4-chlorodiazepam (4-CLD), a ligand of the translocator protein of the outer mitochondrial membrane, increases cardiomyocyte resistance to oxidative stress. We examined the effects 4-CLD, administered at the onset of reperfusion, on microvascular obstruction and cardiac function and structure in a

HIGH FUROSEMIDE DOSE IS AN INDEPENDENT RISK FACTOR FOR MORTALITY IN PATIENTS WITH CHRONIC HEART FAILURE

Diuretics relieve congestion in HF patients but activate the renin-angiotensin-aldosterone system (RAAS). High furosemide doses have been correlated with higher mortality; it is not clear whether higher diuretic doses represent a marker of disease severity or an independent prognostic factor. We

THE ROLE OF INTRAAORTIC BALLOON PUMP AS A BRIDGE TO DECISION FOR PATIENTS WITH ADVANCED STAGE HEART FAILURE DUE TO IDIOPATHIC DILATED CARDIOMYOPATHY

Despite maximal therapy, patients with advanced heart failure frequently experience continuous deterioration, while end organ dysfunction precludes long term mechanical support (LVAD) or transplantation. We examined the role of long term IABP support in unstable patients with idiopathic dilated