Mariantonietta Cicoira

Uric Acid and Survival in Chronic Heart Failure Validation and Application in Metabolic, Functional, and Hemodynamic Staging

Background—Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF). Methods and Results—For the derivation study, 112 patients with CHF (age 59±12 years, peak oxygen consumption [&OV0312;o2] 17±7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (n=182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (n=120). In the derivation study, the best mortality predicting UA cutoff (at 12 months) was 565 &mgr;mol/L (9.50 mg/dL) (independently of age, peak &OV0312;o2, left ventricular ejection fraction, diuretic dose, sodium, creatinine, and urea;P <0.0001). In the validation study, UA ≥565 &mgr;mol/L predicted mortality (hazard ratio, 7.14;P <0.0001). In 16 patients (from both studies) with UA ≥565 &mgr;mol/L, left ventricular ejection fraction ≤25% and peak &OV0312;o2 ≤14 mL/kg per min (MFH score 3), 12-month survival was lowest (31%) compared with patients with 2 (64%), 1 (77%), or no (98%, P <0.0001) risk factor. In an independent study, 51% of patients with MFH score 2 and 81% of patients with MFH score 3 were listed for transplantation. The positive predictive value of not being listed for heart transplantation with an MFH score of 0 or 1 was 100%. Conclusions—High serum UA levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. The relationship between serum UA and survival in CHF is graded. MFH staging of patients with CHF is feasible.

Determinants and Prognostic Value of Left Atrial Volume in Patients With Dilated Cardiomyopathy

OBJECTIVES We aimed to investigate the determinants of left atrial (LA) volume and its prognostic value in patients with dilated cardiomyopathy (DCM). BACKGROUND Enlargement of the LA is a marker of mortality in the general population. Patients with DCM are characterized by a wide range of LA sizes, but the clinical role of this observation has been played down. METHODS A complete echocardiographic Doppler examination was performed in 337 patients (age 60 +/- 13 years; 84% male) with the diagnosis of DCM. Left atrial maximal volume (LA(max)) was measured at left ventricular (LV) end systole (four-chamber view; area-length method). Left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV) and ejection fraction (EF) were also measured. Mitral regurgitation (MR) was graded using a 5-point scale. Mitral E-wave (E) and A-wave (A) velocities, as well as their ratio (E/A), were measured off-line. RESULTS Determinants of LA(max) were: atrial fibrillation (r = 0.34, p < 0.0001), LVEDV (r = 0.46, p < 0.0001), EF (r = 0.40, p < 0.0001), MR (r = 0.39, p < 0.0001), and E/A ratio (r = 0.36, p < 0.0001). During follow-up (41 +/- 29 months), 77 patients died and 12 underwent heart transplantation. Univariate Cox analysis showed that LA(max) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.007-1.013, p < 0.0001), LVESV (HR 1.003, CI 1.001-1.005, p = 0.0003), E/A ratio (HR 1.6, CI 1.3-2.005, p < 0.0001), and MR (HR 1.21, CI 1.03-1.44, p = 0.02) were related to the outcome. On bivariate Cox analysis, LA(max) predicted the prognosis independently of each determinant. Patients with a larger LA volume (LA(max)/m(2) >68.5 ml/m(2)) had a risk ratio of 3.8 compared with those with a smaller LA volume. CONCLUSIONS In patients with DCM, LA volume is associated with LV remodeling, diastolic dysfunction, and the degree of MR. The maximal volume of the LA has an independent and incremental prognostic value, compared with all its determinants.

Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy

Background Functional mitral regurgitation (FMR) is a common finding in patients with heart failure (HF), but its effect on outcome is still uncertain, mainly because in previous studies sample sizes were relatively small and semiquantitative methods for FMR grading were used. Objective To evaluate the prognostic value of FMR in patients with HF. Methods and results Patients with HF due to ischaemic and non-ischaemic dilated cardiomyopathy (DCM) were retrospectively recruited. The clinical end point was a composite of all-cause mortality and hospitalisation for worsening HF. FMR was quantitatively determined by measuring vena contracta (VC) or effective regurgitant orifice (ERO) or regurgitant volume (RV). Severe FMR was defined as ERO >0.2 cm2 or RV >30 ml or VC >0.4 cm. Restrictive mitral filling pattern (RMP) was defined as E-wave deceleration time <140 ms. The study population comprised 1256 patients (mean age 67±11; 78% male) with HF due to DCM: 27% had no FMR, 49% mild to moderate FMR and 24% severe FMR. There was a powerful association between severe FMR and prognosis (HR=2.0, 95% CI 1.5 to 2.6; p<0.0001) after adjustment of left ventricular ejection fraction and RMP. The independent association of severe FMR with prognosis was confirmed in patients with ischaemic DCM (HR=2.0, 95% CI 1.4 to 2.7; p<0.0001) and non-ischaemic DCM (HR=1.9, 95% CI 1.3 to 2.9; p=0.002). Conclusion In a large patient population it was shown that a quantitatively defined FMR was strongly associated with the outcome of patients with HF, independently of LV function.

Cardiorenal Syndrome Type 1: Pathophysiological Crosstalk Leading to Combined Heart and Kidney Dysfunction in the Setting of Acutely Decompensated Heart Failure

Cardiorenal syndrome (CRS) type 1 is characterized as the development of acute kidney injury (AKI) and dysfunction in the patient with acute cardiac illness, most commonly acute decompensated heart failure (ADHF). There is evidence in the literature supporting multiple pathophysiological mechanisms operating simultaneously and sequentially to result in the clinical syndrome characterized by a rise in serum creatinine, oliguria, diuretic resistance, and in many cases, worsening of ADHF symptoms. The milieu of chronic kidney disease has associated factors including obesity, cachexia, hypertension, diabetes, proteinuria, uremic solute retention, anemia, and repeated subclinical AKI events all work to escalate individual risk of CRS in the setting of ADHF. All of these conditions have been linked to cardiac and renal fibrosis. In the hospitalized patient, hemodynamic changes leading to venous renal congestion, neurohormonal activation, hypothalamic-pituitary stress reaction, inflammation and immune cell signaling, systemic endotoxemic exposure from the gut, superimposed infection, and iatrogenesis all contribute to CRS type 1. The final common pathway of bidirectional organ injury appears to be cellular, tissue, and systemic oxidative stress that exacerbate organ function. This review explores in detail the pathophysiological pathways that put a patient at risk and then effectuate the vicious cycle now recognized as CRS type 1.

Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure

OBJECTIVES This study was designed to assess the effects of spironolactone (SP) on left ventricular (LV) function and exercise tolerance in patients with chronic heart failure (CHF). BACKGROUND In severe heart failure (HF), SP improves survival, but the underlying mechanisms are not clear. METHODS We randomized 106 outpatients with HF to SP (12.5 to 50 mg/day) (group 1) or control (group 2). Complete echocardiography and cardiopulmonary exercise testing were performed at baseline and 12 months after randomization. RESULTS Left ventricular end-systolic volume at baseline and at follow-up was 188 +/- 94 ml and 171 +/- 97 ml in group 1 and 173 +/- 71 ml and 168 +/- 79 ml in group 2 (treatment group-by-time interaction, p = 0.03). Left ventricular ejection fraction at baseline and at follow-up was 33 +/- 7% and 36 +/- 9% in group 1 and 34 +/- 7% and 34 +/- 9% in group 2 (treatment group-by-time interaction, p = 0.02). At baseline, 9 patients in group 1 and 3 patients in group 2 had a restrictive mitral filling pattern, a marker of severe diastolic dysfunction; at follow-up, 3 patients in group 1 and no patient in group 2 improved their pattern. No patient in group 1 and 4 patients in group 2 worsened their pattern (chi-square, p = 0.02). Peak oxygen consumption increased significantly in patients treated with 50 mg of SP and decreased in group 2 (17.7 +/- 5.2 vs. 18.5 +/- 5.9 and 19.1 +/- 5.6 vs. 17.9 +/- 5.3, respectively; analysis of variance, p = 0.01). CONCLUSIONS Spironolactone improves LV volumes and function; furthermore, it improves exercise tolerance at the highest administered dose. Our data might explain the mortality reduction during aldosterone antagonism in patients with HF.

Skeletal muscle mass independently predicts peak oxygen consumption and ventilatory response during exercise in noncachectic patients with chronic heart failure

OBJECTIVES We sought to assess whether skeletal muscle mass might be a predictor of peak oxygen consumption (Vo2) and relation of the ventilation to carbon dioxide production (VE/VCo2) slope in patients with chronic heart failure (CHF) independent of clinical conditions, neurohormonal activation and resting hemodynamics. BACKGROUND A variety of abnormalities characterize skeletal muscle and contribute to exercise intolerance in patients with CHF. Skeletal muscle mass is a determinant of peak Vo2 both in healthy patients and in patients with CHF, but there are no reports on the independent predictive value of this parameter, which can be measured with great accuracy by whole-body dual energy X-ray absorptiometry (DEXA). The influence of skeletal muscle mass on VE/VCo2 slope is not known either. METHODS We prospectively evaluated 120 consecutive noncachectic patients with CHF. Every patient underwent a cardiopulmonary exercise test, an echo-Doppler examination and an evaluation of neurohormonal activation and body composition as assessed by DEXA. RESULTS At the univariate analysis, New York Heart Association (NYHA) class (p < 0.0001), age (p < 0.0001), male gender (p < 0.0001) and plasma renin (p < 0.0001) significantly related with peak Vo2. There was a significant correlation between lean mass and absolute peak Vo2 (r = 0.70, p < 0.0001) and VE/VCo2 slope (r = -0.27; p < 0.01). At the multivariate analysis, lean mass predicted peak Vo2 and VE/VCo2 slope independently of NYHA functional class, age, gender, neurohormonal activation and resting hemodynamics. CONCLUSIONS Skeletal muscle mass is an independent predictor of peak Vo2 and VE/VCo2 slope in stable noncachectic patients with CHF. Future studies will determine whether an increase in skeletal muscle mass in the individual patient might result in an improvement in parameters of exercise capacity.

Oxidative stress and hyperuricaemia: pathophysiology, clinical relevance, and therapeutic implications in chronic heart failure

Heart failure (HF) is a state of chronic deterioration of oxidative mechanisms due to enhanced oxidative stress and consequent subcellular alterations. In this condition, oxidant‐producing enzymes, in particular xanthine oxidase (XO), the major cardiovascular source of reactive oxygen species (ROS), are up‐regulated. Growing evidence shows that this impaired oxidative metabolism due to enhanced ROS release is implicated in the development of cardiac hypertrophy, myocardial fibrosis, left ventricular remodelling, and contractility impairment responsible for worsening of cardiac function in CHF. Uric acid (UA) has long been linked with cardiovascular diseases, and hyperuricaemia is a common finding in patients with CHF. Hyperuricaemia is associated with impairment of peripheral blood flow and reduced vasodilator capacity, which relate closely to clinical status and reduced exercise capacity. Recent studies also suggest an association between UA levels and parameters of diastolic function; more importantly, UA has emerged as a strong independent prognostic factor in patients with CHF. In this review, we describe the up‐to‐date experimental and clinical studies that have begun to test whether the inhibition of XO translates into meaningful beneficial pathophysiological changes. This treatment gives evidence that myocardial energy, endothelial dysfunction, and vasodilator reactivity to exercise are improved by reducing markers of oxidative stress responsible for vascular dysfunction, so it represents an interesting therapeutic alternative for better outcome in CHF patients.

Mid-regional pro-adrenomedullin as a novel predictor of mortality in patients with chronic heart failure.

Adrenomedullin (ADM) is a vasodilatory peptide. Its plasma levels or its precursors have not been evaluated in large populations of patients with chronic heart failure (CHF). We sought to explore mid‐regional proADM (MR‐proADM).

Body mass index, prognosis and mode of death in chronic heart failure: results from the Valsartan Heart Failure Trial.

To assess the relationship between body mass index (BMI), mortality and mode of death in chronic heart failure (CHF) patients; to define the shape of the relationship between BMI and mortality.

Exercise intolerance in chronic heart failure: mechanisms and therapies. Part II

Muscular fatigue and dyspnoea on exertion are among the most common symptoms in chronic heart failure; however their origin is still poorly understood. Several studies have shown that cardiac dysfunction alone cannot fully explain their origin, but the contribution of the multiorgan failure present in this syndrome must be highlighted. We aimed to summarize the existing evidence and the most controversial aspects of the complex interplay of different factors involved in the symptom generation. In the first part of the review, six key factors were revised (the heart, the lung, the skeletal muscle, the hormonal changes, the O2 delivery to the periphery, the endothelium). In this second part, the role of the excitatory reflexes and the cardiac cachexia are presented. Finally, potential therapeutic implications are discussed here. We believe that a better knowledge of the pathophysiology of this syndrome may contribute to the management of the patients and to the improvement in their stress tolerance and quality of life.