Roberta Poletti

Clinical significance of chemosensitivity in chronic heart failure: influence on neurohormonal derangement, Cheyne–Stokes respiration and arrhythmias

Increased chemosensitivity has been observed in HF (heart failure) and, in order to clarify its pathophysiological and clinical relevance, the aim of the present study was to investigate its impact on neurohormonal balance, breathing pattern, response to exercise and arrhythmic profile. A total of 60 patients with chronic HF [age, 66+/-1 years; LVEF (left ventricular ejection fraction), 31+/-1%; values are means+/-S.E.M.] underwent assessment of HVR (hypoxic ventilatory response) and HCVR (hypercapnic ventilatory response), neurohormonal evaluation, cardiopulmonary test, 24-h ECG monitoring, and assessment of CSR (Cheyne-Stokes respiration) by diurnal and nocturnal polygraphy. A total of 60% of patients had enhanced chemosensitivity. Those with enhanced chemosensitivity to both hypoxia and hypercapnia (i.e. HVR and HCVR), compared with those with normal chemosensitivity, had significantly (all P<0.01) higher noradrenaline (norepinephrine) and BNP (B-type natriuretic peptide) levels, higher prevalence of daytime and night-time CSR, worse NYHA (New York Heart Association) class and ventilatory efficiency [higher VE (minute ventilation)/VCO(2) (carbon dioxide output) slope], and a higher incidence of chronic atrial fibrillation and paroxysmal non-sustained ventricular tachycardia, but no difference in left ventricular volumes or LVEF. A direct correlation was found between HVR or HCVR and noradrenaline (R=0.40 and R=0.37 respectively; P<0.01), BNP (R=0.40, P<0.01), N-terminal pro-BNP (R=0.37 and R=0.41 respectively, P<0.01), apnoea/hypopnoea index (R=0.57 and R=0.59 respectively, P<0.001) and VE/VCO(2) slope (R=0.42 and R=0.50 respectively, P<0.001). Finally, by multivariate analysis, HCVR was shown to be an independent predictor of both daytime and night-time CSR. In conclusion, increased chemosensitivity to hypoxia and hypercapnia, particularly when combined, is associated with neurohormonal impairment, worse ventilatory efficiency, CSR and a higher incidence of arrhythmias, and probably plays a central pathophysiological role in patients with HF.

Risk factors and prognostic value of daytime Cheyne-Stokes respiration in chronic heart failure patients.

BACKGROUND Sleep-related Cheyne-Stokes (CS) respiration is a known phenomenon in chronic heart failure (CHF). We aimed to study the prevalence, clinical correlates, risk factors and prognostic relevance of daytime CS, as well as its relation with neurohormonal derangement. METHODS One hundred forty seven CHF patients with left ventricular systolic dysfunction (age: 64+/-12 years, ejection fraction, EF, 31+/-8%, mean+/-SD) underwent morning polygraphic recording, in addition to comprehensive clinical and neurohormonal evaluation. RESULTS Daytime CS was detected in 87 patients (59%), and associated with worse NYHA class (2.6+/-0.7 vs 2.2+/-0.8, P<0.05), lower EF (29+/-8 vs 33+/-8%, P<0.05), peak oxygen consumption (11.3+/-8.3 vs 13.4+/-4 mL/min/kg, P<0.05), resting carbon dioxide level (33.1+/-4.2 vs 37.9+/-3.8 mm Hg, P<0.001), higher norepinephrine [588 (395-939) vs (331-681) ng/L, median (interquartile range) P<0.01] and natriuretic peptides [ANP: 136 (57-230) vs 66 (18-103); BNP: 284 (99-510) vs 64 (21-202); NT-proBNP: 2575 (814-3320) vs 448 (147-1599) ng/L, all: P<0.001]. At univariate analysis, CS risk factors were age, EF, carbon dioxide, creatinine, norepinephrine, natriuretic peptides, whereas age and NT-proBNP level were the only multivariate predictors. On a 33-month follow-up, CS resulted among univariate predictors of cardiac death, NT-proBNP emerging as the only variable at multivariate analysis. CONCLUSIONS Daytime CS is frequent in CHF and is correlated with clinical severity, neurohormonal derangement, particularly of NT-proBNP, and long-term prognosis.

Neuro-hormonal activation predicts ventilatory response to exercise and functional capacity in patients with heart failure.

Heart failure (HF) is characterised by reduced tolerance to effort, associated with progressive fatigue and dyspnoea. Neuro‐hormonal activation is a hallmark of HF and influences its clinical evolution.

Prognostic Value of Plasma Renin Activity in Heart Failure

The prognostic role of specific biomarkers of the renin-angiotensin-aldosterone system and sympathetic activation pathways in heart failure has never been investigated in populations with current evidence-weighted treatment. To establish whether the plasma renin activity (PRA), among several neurohormonal biomarkers, is able to predict cardiac events in a population of patients with heart failure on up-to-date treatment, we selected 996 consecutive patients with systolic left ventricular dysfunction (ejection fraction <50%, mean age 65 ± 13 years), who underwent a complete clinical and humoral characterization and were then followed up (median 36 months, range 0 to 72) for cardiac death and appropriate implantable cardioverter device shock. We recorded 170 cardiac deaths and 27 shocks. On Cox multivariate analysis, only ejection fraction (hazard ratio 0.962, 95% confidence interval 0.938 to 0.986), N-terminal pro-brain natriuretic peptide (NT-proBNP; hazard ratio 1.729, 95% confidence interval 1.383 to 2.161) and PRA (hazard ratio 1.201, 95% confidence interval 1.024 to 1.408) were independent predictors of cardiac death. Receiver operating characteristic curve analysis identified a cutoff value for PRA of 2.30 ng/ml/hour that best predicted cardiac mortality. Independent predictors of PRA were ejection fraction, functional class, sodium, potassium, NT-proBNP, norepinephrine, aldosterone, C-reactive protein, and medical therapy. The association of high NT-proBNP and high PRA identified a subgroup (22% of the study population) with the greatest risk of cardiac death. In conclusion, PRA resulted an independent prognostic marker in patients with systolic heart failure additive to NT-proBNP level and ejection fraction. PRA might help to select those patients needing an enhanced therapeutic effort, possibly targeting incomplete renin-angiotensin-aldosterone system blockade.

CMR-verified interstitial myocardial fibrosis as a marker of subclinical cardiac involvement in LMNA mutation carriers.

Lamin A/C ( LMNA ) gene mutation, identified in 10% of familial dilated cardiomyopathy (DCM) patients, is associated with an increased risk of sudden cardiac death (SCD), which may be the first clinical manifestation ([1][1]). Myocardial fibrosis (MF) has been identified in the hearts of LMNA

Prognostic value of plasma renin activity in heart failure patients with chronic kidney disease.

BACKGROUND Impairment of kidney function is frequently observed in chronic heart failure (CHF). It correlates with clinical and neurohormonal status, and affects prognosis. We aimed to identify the prognostic impact of plasma renin activity (PRA) in patients affected by CHF with chronic kidney disease (CKD). METHODS We enrolled 996 consecutive CHF patients (age 65 ± 13 years, mean ± SD, left ventricular ejection fraction, LVEF, 33 ± 10%), who underwent a complete clinical and neurohormonal characterization and were then followed-up (median 36 months) for the end point of cardiac death. RESULTS A stage ≥ 3 CKD (estimated glomerular filtration rate <60 mL/min/1.73 m(2)) was found in 437 patients. Impaired renal function was associated with worse symptoms, lower LVEF, higher plasma norepinephrine, NT-proBNP and PRA (all p<0.001). As compared to patients with preserved renal function, those with CKD had higher cardiac mortality [106 (24%) vs 53 (9.5%), p<0.001]. In CKD patients, at Cox multivariate analysis, only ejection fraction (HR 0.91, 95% CI 0.84-0.97, p=0.008), NT-proBNP (2.53, 1.45-4.41, p=0.001) and PRA (1.73, 1.16-2.58, p=0.007) were independent predictors of cardiac death. ROC analysis identified a cut-off value for PRA of 3.29 ng/mL/h that predicted prognosis with the greatest accuracy. Finally, the elevation of both NT-proBNP and PRA identified a subset of patients with the highest risk of cardiac death. CONCLUSIONS PRA has an independent prognostic value in CHF patients with CKD comorbidity. The combination of PRA and NT-proBNP identifies a group of high risk patients, who might benefit of a more intensive care, targeted to enhance renin-angiotensin system antagonism.

Low triiodothyronine and exercise capacity in heart failure

BACKGROUND Cardiopulmonary exercise test (CPT) has a prominent value in assessing clinical severity in chronic heart failure (HF) patients. Reduced free triiodothyronine (fT3) plasma level is associated with a more severe disease and prognosis. The aim of this study was to evaluate the relationship between low fT3 plasma level and reduced exercise capacity in chronic HF, and to determine the influence of a low T3 status in subsets of patients with different functional impairment. METHODS AND RESULTS 240 HF patients (79% males; age 62 ± 12 years, mean ± standard deviation; left ventricular ejection fraction, EF, 30 ± 9%) underwent a CPT, clinical and neurohormonal characterization (assay for plasma brain natriuretic peptide, BNP, norepinephrine, aldosterone, renin activity, fT3, free T4, thyroid-stimulating hormone). At multivariate analysis in the whole population, age, gender and BNP level were independently associated with peak VO2, whereas in patients with severe functional impairment (peak VO2 < 14 ml/min/kg) fT3 resulted independently related to peak VO2, together with gender and BNP. When patients with peak VO2 < 14 ml/min/kg were divided according to fT3 levels, patients with low T3 syndrome showed reduced exercise capacity and worse ventilatory efficiency. CONCLUSIONS BNP and fT3 are independently associated with exercise capacity in severely compromised HF patients.

Clinical relevance of non-cardiac determinants of natriuretic peptide levels.

Abstract There is evidence that natriuretic peptide (namely atrial and/or B-type natriuretic peptides) plasma concentration may be elevated in many clinical conditions besides cardiovascular diseases, the most frequent being lung diseases, renal and liver failure, acute cerebrovascular events, acute and chronic inflammatory diseases and certain metabolic and endocrine disorders. In general, increased circulating levels of natriuretic peptides (compared to the normal range of a healthy population) may be considered expression of activation of the neuro-endocrine system, which can be the cause or consequence of cardiac stressor events. Furthermore, some variables, such as gender and obesity, may affect natriuretic peptide secretion and plasma concentration by completely extra-cardiac mechanisms. Increased expression of the natriuretic peptide system, counteracting neuro-hormonal and immunological activation, may occur in many clinical conditions, as witnessed by the considerable number of diseases in which the natriuretic peptide system has been found to be altered. Several studies have demonstrated that higher circulating levels of natriuretic peptides represent a strong independent risk factor for major cardiovascular complications and/or death, even in extra-cardiac diseases. Because several of these diseases may be present in patients with left ventricular dysfunction, the possible influence on diagnostic and prognostic accuracy of natriuretic peptides in heart failure will be discussed. Clin Chem Lab Med 2008;46:1515–23.

Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible?

Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of biomarkers of the RAAS activation, as a guide to tailor individual therapy in the current practice, and their implementation as a rule-in marker for future trials on novel drugs in the heart failure setting.

Daptomycin concentrations in valve tissue and vegetation in patients with bacterial endocarditis

ABSTRACT In a patient with mitral-aortic native-valve Streptococcus oralis endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 μg/g, respectively, and 26 μg/g in the mitral vegetation. In the case of porcine-aortic-valve Staphylococcus epidermidis endocarditis, the daptomycin concentrations were 53.1 μg/g in the valve and 18.1 μg/g in perivalvular tissues. Daptomycin achieved apparently adequate tissue concentrations. S. epidermidis was eradicated, whereas Streptococcus oralis persisted, and its daptomycin MIC displayed a 4-fold increase.