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.

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.

Prognostic value of angiopoietin-2 in patients with chronic heart failure.

PURPOSE: The analysis of biomarkers with a prognostic value in chronic heart failure (CHF) is in constant progress. This study aimed to evaluate the short-term prognostic value of angiopoietin-2 (Ang2), galectin-3 (Gal-3), myeloperoxidase (MPO), endostatin (End), and pro-brain natriuretic peptide (pro-BNP) as a conventionally accepted prognosis biomarker in CHF patients. METHODS AND RESULTS: 146 consecutive patients with CHF due to left ventricular systolic dysfunction (LVEF<40% at echocardiography) were enrolled, and underwent serum/blood sample analysis after 12-h fasting. Within 1year, 25 (17%) patients died (D) or underwent heart transplantation (HT). D+HT patients showed higher values of Ang2 (Log Ang2: 8.97±0.52 vs. 8.45±0.69, p=0.0004), myeloperoxidase (MPO) (Log MPO: 5±1.1 vs. 4.2±1.3, p=0.005) and pro-BNP (Log pro-BNP: 8.70±0.9 vs. 7.45±1.3, p<0.00001). At univariate Cox regression, pro-BNP and Ang2 were the best predictors of 1-year mortality, with area under the curve (AUC)=0.78 for pro-BNP (68% sensitivity and 82% specificity to predict outcome for a cut-off value of 5109pg/mL, 95% confidence interval [CI] 0.70-0.85, p<0.0001) and AUC=0.73 for Ang2 (84% sensitivity and 61% specificity to predict outcome for a cut-off value of 5175pg/mL, 95% CI 0.65-0.80, p<0.0001). At multivariate analysis, pro-BNP was the only predictor of one-year D/HT. CONCLUSION: In our series of CHF patients, Ang2 and pro-BNP showed the best predictive value for 1-year outcome, while only pro-BNP could independently predict D/HT.

Long-term echocardiographic and cardioscintigraphic effects of growth hormone treatment in adults with Prader-Willi syndrome.

CONTEXT: In Prader-Willi syndrome (PWS), an altered GH secretion has been related to reduced cardiac mass and systolic function compared to controls. OBJECTIVE: The objective was to evaluate the cardiovascular response to a 4-year GH therapy in adult PWS patients. STUDY PARTICIPANTS: Study participants were nine severely obese PWS adults (three females, six males) and 13 age-, gender-, and body mass index-matched obese controls. METHODS: In an open-label prospective study, assessment of endocrine parameters and metabolic outcome, whole-body and abdominal fat scans, echocardiography, and radionuclide angiography in unstimulated and dobutamine-stimulated conditions were conducted at baseline and after 1 and 4 years of GH treatment. RESULTS: GH treatment increased IGF-1 (P < .0001), decreased C-reactive protein levels (P < .05), improved visceral fat mass (P < .05), and achieved near-significant changes of fat and fat-free body mass in PWS patients. Left ventricle mass indexed by fat mass increased significantly after 1 and 4 years of GH therapy (P < .05) without evident abnormalities of diastolic function, while a trend toward a reduction of the ejection fraction was documented by echocardiography (P = .054). Radionuclide angiography revealed stable values throughout the study of both the left and right ventricle ejection fractions, although this was accompanied by a statistically nonsignificant reduction of the left ventricle filling rate. A positive association between lean body mass and left ventricle ejection fraction was evident during the study (P < .05). CONCLUSIONS: GH therapy increased the cardiac mass of PWS adults without causing overt abnormalities of systolic and diastolic function. Although the association between lean mass and left ventricle ejection fraction during GH therapy corroborates a favorable systemic outcome of long-term GH treatment in adults with PWS, subtle longitudinal modifications of functional parameters advocate appropriate cardiac monitoring in the long-term therapeutic strategy for PWS.

Fibrosis markers and CRIM1 increase in chronic heart failure of increasing severity.

BACKGROUND: Fibrosis suppressors/activators in chronic heart failure (CHF) is a topic of investigation. AIM: To quantify serum levels of fibrosis regulators in CHF. METHODS: ELISA tests were used to quantify fibrosis regulators, procollagen type-(PIP)I, (PIP)III, collagen-I, III, BMP1,2,3,7, SDF1α, CXCR4, fibulin 1,2,3, BMPER, CRIM1 and BAMBI in 66 CHF (NYHA class I, n = 9; II, n = 34; III n = 23), and in 14 controls. RESULTS: In CHF, TGFßR2, PIPIII, SDF1α and CRIM1 were increased. PIPIII correlated with CRIM1. CONCLUSIONS: The BMPs inhibitor CRIM1 is increased and correlates with higher levels of serum PIPIII showing an imbalance in favor of pro-fibrotic mechanisms in CHF.

Aerobic training and angiogenesis activation in patients with stable chronic heart failure: a preliminary report.

The pathophysiology of chronic heart failure (CHF) involves multiple hystologic and molecular alterations. To determine the effects of physical training on circulating endothelial progenitor cells (EPCs), angiogenesis (angiogenin, angiopoietin-1 and -2, VEGF, Tie-2, SDF-1α) and inflammation (IL-6, CRP), we compared data obtained from 11 CHF pts before and after 3 months aerobic exercise training, to those from 10 non trained CHF pts (CHF-C group, age 64 + 2 years, NYHA 2). At the end of the study, EPCs count and AP-2 serum levels significantly increased in the CHF-TR group. These preliminary data suggest a significant effect of even a short program of physical training on angiogenic activation and endothelial dysfunction.

Flow-mediated dilation normalization predicts outcome in chronic heart failure patients.

BACKGROUND: Reduced flow-mediated dilation (FMD) is a known prognostic marker in heart failure (HF), but may be influenced by the brachial artery (BA) diameter. Aiming to adjust for this influence, we normalized FMD (nFMD) by the peak shear rate (PSR) and tested its prognostic power in HF patients. METHODS AND RESULTS: BA diameter, FMD, difference in hyperemic versus rest brachial flow velocity (FVD), PSR (FVD/BA), and nFMD (FMD/PSR × 1000) were assessed in 71 HF patients. At follow-up (mean 512 days), 19 HF (27%) reached the combined endpoint (4 heart transplantations [HTs], 1 left ventricle assist device implantation [LVAD], and 14 cardiac deaths [CDs]). With multivariate Cox regression analysis, New York Heart Association functional class ≥III (hazard ratio [HR] 9.36, 95% confidence interval [CI] 2.11-41.4; P = .003), digoxin use (HR 6.36, 95% CI 2.18-18.6; P = .0010), FMD (HR 0.703, 95% CI 0.547-0.904; P = .006), PSR (HR 1.01, 95% CI 1.005-1.022; P = .001), FVD (HR 1.04, 95% CI 1.00-1.06; P = .02), and nFMD (HR 0.535, 95% CI 0.39-0.74; P = .0001) were predictors of unfavorable outcome. Receiver operating characteristic curve for nFMD showed that patients with nFMD >5 seconds had significantly better event-free survival than patients with nFMD ≤5 seconds (log-rank test: P < .0001). CONCLUSIONS: nFMD is a strong independent predictor of CD, HT, and LVAD in HF with left ventricular ejection fraction <40%. Patients with nFMD >5 seconds have a better prognosis than those with lower values.

Stepwise increase of angiopoietin-2 serum levels is related to haemodynamic and functional impairment in stable chronic heart failure.

BACKGROUND: A reciprocal link between inflammation, oxidative/nitrosative stress, and endothelial dysfunction has been postulated in chronic heart failure (CHF). The endothelial repair mechanisms involved remain to be determined. Our aim was to investigate whether there are detectable signs of ongoing angiogenesis in serum of CHF patients and to evaluate the correlation with indexes of haemodynamic and functional impairment. METHODS AND RESULTS: Enzyme-linked immunosorbent assay tests were used to quantify angiogenin, angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, Tie-2, and brain natriuretic peptide in serum of 87 patients with CHF of increasing severity according to New York Heart Association (NYHA; class I, n = 8; II, n = 45; and III, n = 34) and in 14 healthy subjects matched for age and sex. Angiogenin, angiopoietin-2, and Tie-2 were significantly increased in CHF of increasing severity (Kruskal-Wallis: p = 0.0004, p < 0.0001, and p = 0.017, respectively). Angiopoietin-2 was inversely correlated with the 6-min walking test (r = -0.65, p < 0.0001), peak oxygen consumption (VO(2max); r = -0.57, p = 0.0002), and deceleration time (r = -0.61, p < 0.0001). Multiple regression analysis showed that angiopoietin-2 was mainly associated with VO(2max) (p = 0.018). The angiopoietin-2 area under the receiver operating characteristic curve for CHF diagnosis was 0.94 (95% CI 0.88-0.99; p < 0.001). CONCLUSIONS: These data demonstrate that angiopoietin-2 and selected serum markers of angiogenesis progressively increase with haemodynamic and functional decline in CHF.

Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues.

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.

Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial.

AIMS: The GISSI-HF trial showed that n-3 polyunsaturated fatty acids (PUFA), but not rosuvastatin, reduce morbidity and mortality in patients with symptomatic heart failure (HF) of any cause. The aim of this echocardiographic substudy of GISSI-HF was to investigate the effects of n-3 PUFA and of rosuvastatin on left ventricular (LV) function in such patients. METHODS AND RESULTS: Six hundred and eight chronic HF patients were randomized to n-3 PUFA (n=312) or placebo (n=296); a second randomization was performed to rosuvastatin (n=212) or placebo (n=207). Echocardiographic examinations were recorded at baseline and at 1, 2, and 3 years; offline analysis was performed by a core laboratory to ensure consistent quantitative analysis. Baseline LV ejection fraction (EF) was 30% (95%CI 29-31). Left ventricular ejection fraction increased with n-3 PUFA by 8.1% at 1 year, 11.1% at 2 years, and 11.5% at 3 years vs. 6.3% at 1 year, 8.2% at 2 years, and 9.9% at 3 years in the placebo group (P=0.0050). No other echocardiographic parameter changed significantly. Rosuvastatin effects were not statistically significant. CONCLUSION: n-3 PUFA can provide a small but statistically significant advantage in terms of LV function in patients with symptomatic HF of any aetiology, already treated with recommended therapies.

Doppler echocardiography in advanced systolic heart failure: a noninvasive alternative to Swan-Ganz catheter.

BACKGROUND: Although several studies have demonstrated a good correlation between Doppler echocardiographic and invasive measurements of single hemodynamic variables, the accuracy of echocardiography in providing a comprehensive assessment in individual patients has not been validated. The aim of this study was to assess the accuracy and clinical applicability of Doppler echocardiography in determining the entire hemodynamic profile in stable patients with advanced systolic heart failure. METHODS AND RESULTS: Doppler echocardiography and Swan-Ganz catheterization were simultaneously performed in 43 consecutive patients with advanced heart failure. Echocardiographic data required for estimation of right atrial, pulmonary artery systolic, and pulmonary capillary wedge pressures; cardiac output; and pulmonary vascular resistance were obtained and compared with hemodynamic data. For all variables, invasive and noninvasive hemodynamic values were highly correlated (P<0.0001), with very low bias and narrow 95% confidence limits. In 16 patients with elevated pulmonary vascular resistance (>3 Wood U) and pulmonary capillary wedge pressures (>20 mm Hg) at baseline, hemodynamic and Doppler measurements were simultaneously repeated after unloading manipulations. Absolute values and changes of pulmonary vascular resistance and pulmonary capillary wedge pressures after unloading were still accurately predicted (r =0.96 and r =0.92, respectively). CONCLUSIONS: Doppler echocardiography may offer a valid alternative to invasive cardiac catheterization for the comprehensive hemodynamic assessment of patients with advanced heart failure, and it may assist in monitoring and optimization of therapy in potential heart transplant recipients.

Role of oxidative and nitrosative stress biomarkers in chronic heart failure.

In this review, we present recent insights on chronic heart failure (CHF) and the potential role of tumor necrosis factor (TNF)-alpha, interleukins, myeloperoxidase (MPO), and nitrosative stress in the progression of this disease process. Reactive oxygen species (ROS) are produced as a consequence of aerobic metabolism. Under physiologic conditions, their unfavourable effect in causing oxidative damage is counteracted by antioxidants. An imbalance in favour of oxidants leads to oxidative stress, and contributes to myocyte apoptosis, direct negative inotropic effects, and reduced bioavailability of nitric oxide (NO). Together, these effects lead to impaired vasodilatation of the coronary, pulmonary and peripheral vascular beds. In patients with moderate to severe forms of CHF, TNF-alpha leads to the formation of nitrotyrosine and consumption of nitric oxide by virtue of activation of myeloperoxidase. Further studies are required to better elucidate the complex interaction of oxidative stress, endothelial dysfunction and inflammatory activation in CHF. Such insights would likely lead to development of better strategies for the assessment of the disease severity by monitoring of new bio-humoral indices and better treatment approaches.

Role of endothelial cell stress in the pathogenesis of chronic heart failure.

Endothelial cells are key modulators of diverse physiological processes, and their impaired function is a cause of numerous cardiovascular diseases. Under physiologic condition, the reactive oxygen and nitrogen mediators in endothelia lead to the signal propagation of the initial stimulus, by forming molecules with a longer half-life like hydrogen peroxide. Hydrogen peroxide is the focus of growing attention in endothelial biology, and consequently the enzymes involved in its generation and clearance are viewed as novel mediators of great importance. In particular, among peroxidases, myeloperoxidase is recognized as a key enzyme, capable of impairing intracellular NO reservoirs as well as producing oxidized amino acids such as 3-chlorotyrosine or 3-nitrotyrosine. This process switches the functional pathways from normal signalling to a condition characterized by oxidative and/or nitrosative stress. Understanding the molecular mechanisms involved in these stress responses in endothelium will lead to better therapeutic strategies for oxidative stress-driven cardiovascular diseases.

Oxidative stress induces myeloperoxidase expression in endocardial endothelial cells from patients with chronic heart failure.

Increased oxidative stress has been implicated in the pathogenesis of a number of cardiovascular diseases. Recent findings suggest that myeloperoxidase (MPO) may play a key role in the initiation and maintenance of chronic heart failure (CHF) by contributing to the depletion of the intracellular reservoir of nitric oxide (NO). NO consumption through MPO activity may lead to protein chlorination or nitration, leading to tissue damage. Primary cultures of human endocardial endothelial cells (EEC) obtained at heart transplantation of patients with CHF and human umbilical vein endothelial cells (HUVEC) were subjected to oxidative stress by incubation with hydrogen peroxide at non lethal (60 microM) dose for different exposure times (3 and 6 h). Treated and control cells were tested by immunohistochemistry and RT-PCR for MPO and 3-chlorotyrosine expression. Both endothelial cell types expressed myeloperoxidase following oxidative stress, with higher levels in EEC. Moreover, 3-chlorotyrosine accumulation in treated cells alone indicated the presence of MPO-derived hypochlorous acid. Immunohistochemistry on sections from post-infarcted heart confirmed in vivo the endothelial positivity to MPO, 3-chlorotyrosine and, to a minor extent, nitrotyrosine. Immunohistochemical observations were confirmed by detection of MPO mRNA in both stimulated EEC and HUVEC cells. This study demonstrates for the first time that EEC can express MPO after oxidative stress, both in vitro and in vivo, followed by accumulation of 3-chlorotyrosine, an end product of oxidative stress. Deregulation of endothelial functions may contribute to the development of a number of cardiovascular diseases, including CHF. The results also highlight the notion that endothelium is not only a target but also a key player in oxidative-driven cardiovascular stress.

Increased nitrotyrosine plasma levels in relation to systemic markers of inflammation and myeloperoxidase in chronic heart failure.

The presence of a reciprocal link between inflammation and oxidative/nitrosative stress has been postulated in chronic heart failure (CHF). We aimed to determine signs of nitrosative stress in serum/plasma of CHF patients. ELISA tests were used for quantification of serum/plasma levels of Nitrotyrosine (NT), H(2)O(2), total NO, nitrite (NO(2)(-)), myeloperoxidase (MPO), Tumor Necrosis Factor-alpha (TNFalpha) and pro-Brain Natriuretic Peptide (proBNP) in 66 CHF patients (9 in NYHA I, 34 NYHA II, 23 NYHA III) and in 14 age-matched healthy subjects. NT levels were higher in NYHA III CHF patients compared to NYHA II (p<0.05), NYHA I (p<0.03) and controls (p<0.02), whereas NO(2)(-) and total NO were higher in NYHA III compared to I (p<0.05 and p<0.04, respectively) and controls (p<0.004 and 0.002) and in NYHA II compared to controls (p<0.04 and p<0.009). NT levels correlated significantly with MPO (r=0.37, p<0.003), TNFalpha (r=0.32, p<0.01) and proBNP (r=0.32, p<0.01). These data demonstrate an increased NT plasma level in patients with moderate/severe CHF which is associated to increased levels of markers of systemic inflammation.

Determination of the acceptable MPEG-4 quality for clinical real-time tele-echocardiography services.

UNLABELLED: The characteristics of Moving Picture Experts Group (MPEG-4) video compression, in particular its adaptability to narrowband channels and the elevated degree of compression obtainable, make it of interest for services of telemedicine that require instantaneous video transmission and interpretation. In this study we faced the problem of the minimum quality of service (QoS) in specific applications of tele-echocardiography (T-E). In the specifics we evaluated the clinical adequacy of MPEG-4 compression in the real time transmission of echocardiographic studies. Forty echocardiographic examinations consisting of standard projections of patients affected by ischemic heart disease were submitted to two observers expert in echocardiography, who made 4 separate evaluations as follows: 2 on the same equipment on which the original studies were performed; 1 after online MPEG-4 codification of the studies at 256 kb/s; 1 after online MPEG-4 codification of the studies at 128 kb/s. For each evaluation, the following data were collected: subjective opinion on the overall visual quality of the images; estimate of ejection fraction and level of impairment; wall Motion Score Index and percentage of asynergy; mitral failure. THE RESULTS: 1) the subjective quality of the echocardiographic images was the same as that perceived in the video at Mpeg4/256 kb/s compression level while it was lower, as expected, in the video Mpeg4/128 kb/s; 2) the quality degradation did not produce a statistically significant difference in the evaluation of left ventricular function and regional wall motion impairments. These results confirm the feasibility of MPEG-4 compression for the transmission of echocardiographic studies for use in telemedicine and suggest that it is not necessary to seek transmission speeds higher than 256 kb/s for the semiquantitative reading of left ventricular kinetics.

Perioperative and postoperative predictors of outcome in patients with low ejection fraction early after coronary artery bypass grafting: the additional value of left ventricular remodeling.

BACKGROUND: Scant data exist on factors that may identify outcome in patients with severe left ventricular (LV) dysfunction early after coronary artery bypass graft surgery (CABG). DESIGN: This study was designed to determine the prognostic value of clinical, operative, and postoperative factors in patients with LV dysfunction early after CABG. METHODS: In 333 consecutive patients with ejection fraction < or =35% on admission to residential cardiac rehabilitation after isolated CABG, potential preoperative, perioperative, and postoperative predictors of outcome, including 6-month LV remodeling, were recorded and patients followed up for a median of 3 years. The study end points were cardiovascular (CV) mortality and the combination of CV mortality and nonfatal CV events requiring hospitalization. RESULTS: The 3-year CV mortality-free survival and survival free of nonfatal CV event rates were 87 and 73%, respectively. Independent predictors of CV mortality were history of congestive heart failure [hazard ratio, HR: 2.8; 95% Confidence Interval (CI): 1.51-5.21], low ejection fraction on admission to cardiac rehabilitation (HR: 0.9; 95% CI: 0.87-0.96), and early complications after CABG (HR: 2.5; 95% CI: 1.23-5.15). When the combined end points were considered, postoperative left atrial size (HR: 1.07; 95% CI: 1.01-1.11), New York Heart Association class III or IV (HR: 1.69; 95% CI: 1.04-2.74), and 6-month remodeling (HR: 2.12; 95% CI: 1.33-3.36) were independent predictors. CONCLUSION: Simple preoperative and postoperative variables may help identify patients with LV dysfunction early after CABG who are still at risk of major CV events. In this setting, 6-month LV remodeling is a strong predictor of a poor prognosis.

Conditional cardiovascular response to growth hormone therapy in adult patients with Prader-Willi syndrome.

CONTEXT: In Prader-Willi syndrome (PWS), an altered GH secretion has been related to reduced cardiac mass and systolic function when compared with controls. OBJECTIVES: The objective of the study was to evaluate the cardiovascular response to GH therapy in adult PWS patients. STUDY PARTICIPANTS: Thirteen obese PWS adults (seven males and six females, aged 26.9+/-1.2 yr, body mass index 46.3+/-1.6 kg/m2) participated in the study. METHODS: Determination of IGF-I, metabolic parameters, echocardiography, and cardioscintigraphy with dobutamine stimulation was made during 12 months GH therapy, with results analyzed by repeated-measures ANOVA. RESULTS: GH therapy increased IGF-I (P<0.0001); decreased C-reactive protein levels (P<0.05); and improved lean mass (P<0.001), fat mass (P<0.05), and visceral fat (P<0.001). Echocardiography showed that 6- and 12-month GH therapy increased left ventricle mass in 76 and in 61% of patients, respectively (P<0.05), did not change diastolic function, and slightly decreased the left ventricle ejection fraction (LVEF) (P=0.054). Cardioscintigraphy documented stable values of LVEF throughout the study, whereas right ventricle ejection fraction decreased significantly (P<0.05) being normally responsive to dobutamine infusion. A positive association between IGF-I z-scores and LVEF occurred at the 6- and 12-month follow-up (P<0.05). CONCLUSIONS: In PWS, GH therapy increased cardiac mass devoid of diastolic consequences. The observation of a slight deterioration of right heart function as well as the association between IGF-I and left ventricular function during GH therapy suggest the need for appropriate cardiac and hormonal monitoring in the therapeutic strategy for Prader-Willi syndrome.

The impact of growth hormone/insulin-like growth factor-I axis and nocturnal breathing disorders on cardiovascular features of adult patients with Prader-Willi syndrome.

CONTEXT: Adult patients with Prader-Willi syndrome (PWS) are prone to develop obesity, GH deficiency (GHD), and their related complications, with cardiopulmonary failure explaining more than half of PWS fatalities. OBJECTIVE AND STUDY PARTICIPANTS: This study was undertaken to examine the effect of GHD and sleep breathing disorders on cardiovascular risk factors and heart features of 13 PWS (age 26.9 +/- 1.2 yr) and 13 age-, gender-, and body mass index-matched obese individuals (age 26.2 +/- 0.8 yr). RESULTS: Compared with controls, PWS patients had lower GH response to arginine+GHRH, IGF-I levels, triglycerides, total and LDL-cholesterol, insulin, and insulin resistance measured by a homeostatic model approach. Dual-energy x-ray absorptiometry, abdominal computed tomography scans, and polysomnography revealed a greater fat mass, similar abdominal fat, but greater sleep breathing disorders in PWS than obese subjects. Echocardiography showed no systolic or diastolic alteration, although PWS had lower left ventricle (LV) mass (135.7 +/- 7.7 vs. 163.5 +/- 8.4 g, P < 0.05) and near significantly lower values of LV end-diastole diameter (P = 0.08), compared with obese controls. Baseline radionuclide angiography documented comparable values of systolic and diastolic values between groups. However, adrenergic stimulation with dobutamine caused a lower increase of LV ejection fraction (71.9 +/- 1.9 vs. 76.3 +/- 1.2%, P < 0.05) and heart rate (103 +/- 6.9 vs. 128 +/- 2.8 beats/min, P < 0.05) in PWS than obese individuals. By multivariate analysis, nocturnal oxygen desaturation and IGF-I levels were main significant predictors of LV mass and heart rate in PWS patients. CONCLUSIONS: PWS differs from simple obesity by a healthier metabolic profile, impaired nocturnal breathing, decreased heart geometry, and systolic and chronotropic performance. GHD and the predictive role of IGF-I on structural and functional heart parameters suggest a GH/IGF-I-mediated control of cardiac risk in PWS.

Limited predictive value of cardiopulmonary exercise indices in patients with moderate chronic heart failure treated with carvedilol.

BACKGROUND: Peak oxygen consumption (VO2) is traditionally used for risk stratification in chronic heart failure (CHF); however, its predictive value is unknown with carvedilol treatment. Therefore, we sought to investigate the prognostic role of gas-exchange parameters obtained from symptom-limited cardiopulmonary exercise testing (CPX) in patients with CHF that is treated with carvedilol. METHODS: A total of 508 consecutive patients (443 men, mean age [+/- SD] 59 +/- 9 years) with a mean left ventricular ejection fraction (LVEF) of 25% +/- 7% underwent CPX. The peak VO2 was 13.9 +/- 3 mL/kg/min; the rate of increase of minute ventilation per unit of increase of carbon dioxide production (VE/VCO2 slope) was 32 +/- 2. Outcomes (cardiovascular death or urgent heart transplantation) were determined when all patients who survived had been observed for a minimum of 6 months. RESULTS: Patients were divided into groups according to treatment (carvedilol and non-carvedilol); 236 patients were treated with carvedilol (46%), at a mean dose of 25 +/-13 mg. The VE/CO2 slope, LVEF, peak VO2, and carvedilol treatment were revealed by means of multivariate analysis to be independent and additional predictors in the total population; VE/VCO2 slope, LVEF, and peak VO2 were revealed to be independent and additional predictors in the patients in the noncarvedilol group (all P <.001); and only peak VO2 was revealed to be an independent and additional predictor in the patients in the carvedilol group (P <.01). In the carvedilol group, mortality rates were 26%, 11%, 10%, and 4% (P <.05) in patients with peak VO2 < or =10 mL/kg/min, >10 to < or =14 mL/kg/min, >14 to 18 mL/kg/min, and > or =18 mL/kg/min, respectively. No difference in mortality rates according to peak VO2 or additional outcome indices were identified in the 212 patients with peak VO2 >10 mL/kg/min. CONCLUSIONS: Peak VO2 provides limited predictive information in patients with CHF that is treated with carvedilol, and no additional gas exchange parameter yields supplementary advice.