Alessandra Gabutti

Silent myocardial damage in cocaine addicts

Background Cocaine addiction is associated with either ischaemic or non-ischaemic cardiac complications. The prevalence of myocardial damage in asymptomatic addicts has never been evaluated by cardiovascular magnetic resonance (CMR), which allows non-invasive detection of myocardial oedema and fibrosis. Objective To prospectively evaluate the prevalence of myocardial damage in cocaine addicts with no history of cardiac disease by CMR. Methods Thirty consecutive subjects (25 men, mean age 39±7 years), with no history of cardiac symptoms/disease were evaluated 48 h after the withdrawal of cocaine by a comprehensive humoral, clinical and instrumental assessment, including B-type natriuretic peptide and troponin I assay, echocardiography, exercise stress test and 24 h ECG recording, as well as CMR examination. The CMR study was performed using a 1.5 Tesla scanner. Myocardial oedema was evaluated by a T2-weighted STIR sequence and fibrosis using the late gadolinium enhancement technique. Results Biohumoral markers of cardiac involvement were negative in all subjects except one. Fifteen subjects had subtle abnormalities at resting ECG, while exercise stress testing and Holter studies were negative for ischaemic or arrhythmic events. Echocardiography provided evidence of wall motion abnormalities in 12 subjects. At CMR evaluation, myocardial involvement was detected in 25 subjects (83%), oedema in 14 (47%) and fibrosis in 22 (73%). Eleven subjects (37%) showed both myocardial oedema and fibrosis with similar localisations in nine. Seven subjects had ischaemic patterns of fibrosis and 15 had non-ischaemic patterns of fibrosis. Conclusions A high prevalence of cardiac damage in asymptomatic cocaine addicts can be found by CMR examination.

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.

Markers of fibrosis, inflammation, and remodeling pathways in heart failure

Ventricular remodeling occurs progressively in untreated patients after large myocardial infarction and in those with cardiomyopathy. The pathologic changes of increased left ventricular (LV) volume and perturbation in the LV chamber geometry involve not only the myocytes, but also the non-myocyte cells and the extracellular matrix. Inflammation, fibrosis, neuro-hormonal activation, and ongoing myocardial damage are the mechanisms underlying remodeling. The detection of an ongoing remodeling process by means of biomarkers such as cytokines, troponins, neurohormones, metalloproteinases, galectin-3, ST-2 and others, may hold a clinical value and could, to some extent, drive the therapeutical strategy in patients after a myocardial infarction or with heart failure. For this reason, there is an increasing interest in the development of new biomarkers and a great number of laboratory tests have been recently proposed, whose clinical usefulness, however, is not fully established yet.

C-type natriuretic peptide expression in patients with chronic heart failure: effects of aerobic training

Background C-type natriuretic peptide (CNP) is structurally related to cardiac natriuretic peptides and is currently considered as an endothelium-derived hyperpolarizing factor. Endothelial dysfunction, commonly observed in chronic heart failure (HF) patients is positively affected by physical training. Methods To evaluate the effect of aerobic physical training on the expression of CNP, 90 HF patients on optimal pharmacological treatment (age 62±2 years, mean±SEM), randomly assigned in a 3:1 ratio to either control group (C, 19 patients) or home-based aerobic exercise-training program group (T, 71 patients), completed the protocol. Plasma assay of CNP, brain natriuretic peptide or B-type natriuretic peptide (BNP), and norepinephrine; echocardiogram; and cardiopulmonary-stress test were performed in all patients at enrollment and after 9 months. Results At baseline, in both groups, CNP plasma level was significantly related to BNP (R = 0.50), ejection fraction (R = 0.43), and peak oxygen uptake (Vo2, R = 0.43, all P [ 0.001). After 9 months, trained patients showed an improvement in peak Vo2 (P [ 0.001) and ejection fraction (P [ 0.05), whereas norepinephrine (P [ 0.05), BNP (P [ 0.001), and CNP (P [ 0.001) decreased. No changes occurred in group C in group T, the decrease in CNP was significantly related to the increase in peak Vo2 (R = 0.31, P [ 0.01), and the relation between CNP and BNP was preserved at the end of the program (R = 0.41, P [ 0.001). Conclusion Clinical and functional improvement after physical training in HF patients is associated with a decrease in adrenergic activation and in both CNP and BNP concentration. Changes in CNP plasma concentration after physical training might reflect an improvement in endothelial function.

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.

Atrial fibrillation and amino-terminal pro-brain natriuretic peptide as independent predictors of prognosis in systolic heart failure.

BACKGROUND Survival of patients with systolic heart failure (HF) may be influenced by the presence of chronic atrial fibrillation (AF) and circulating concentrations of B-type natriuretic peptides. In this study, we sought to assess the prognostic value of chronic AF in comparison to those of amino-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels and of echocardiographic parameters among HF patients of the entire study population and in those with AF. METHODS Plasma NT-proBNP levels and echocardiography were prospectively assessed in 489 patients with chronic systolic HF (LV ejection fraction <or=45%) in sinus rhythm or AF (16%). Follow-up duration was 26+/-15 months. RESULTS Patients with AF were older (p<0.0001), had a worse NYHA class (p=0.002) and higher NT-proBNP levels (p<0.0001) than those in sinus rhythm. Presence of AF (HR [hazards ratio]: 2.01, p=0.013) and plasma NT-proBNP (HR: 3.05, p<0.0001) were the only independent predictors of all-cause mortality. At receiver operating characteristic analyses, the threshold level for outcome prediction of NT-proBNP was higher in patients with AF (3883 pg/ml) than in patients in sinus rhythm (1653 pg/ml). Multivariate analysis performed in patients with HF and AF showed that plasma NT-proBNP was the most important predictor of death after statistic adjustment for age. CONCLUSIONS Chronic AF and NT-proBNP independently predicted the outcome of patients with HF. The threshold level of NT-proBNP for outcome prediction was different in patients with AF with respect to those in sinus rhythm. NT-proBNP was the most important independent predictor of all-cause mortality in HF patients with AF.

Statin intolerance in heterozygous familial hypercolesterolemia with cardiovascular disease: After PCSK-9 antibodies what else?

Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 ± 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a)-hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 ± 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 ± 4 weeks) of therapy, a decrease in total cholesterol (–35%), LDL cholesterol (–51%) and Lp(a) levels (–20%) was observed. Five out of 18 patients reached LDL cholesterol levels of <70 mg/dl, seven showed LDL cholesterol values between 71 and 100 mg/dl, and six out of 18 still had LDL cholesterol levels above 100 mg/dl. Among the six patients with LDL cholesterol levels >100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era.

Natriuretic peptide testing in primary care patients.

Abstract The evaluation of cardiac endocrine function by means of automated robust assays has permitted the introduction of a cheap and powerful clinical tool. Plasma concentration of B-type-related natriuretic peptides is a marker of either hemodynamic or neurohormonal stress on the heart and has been validated within the diagnostic and prognostic domain in patients with suspected or ascertained heart failure, mostly in the in-hospital setting. Evidence is growing, supporting an out-of-hospital use, namely in primary care. Its implementation in this setting in screening programs and diagnostic algorithms might contribute to decrease the apparent disparity between the general practitioner and the specialist approach to disease management. Clin Chem Lab Med 2008;46:1533–42.

Glycosylated haemoglobin is associated with neurohormonal activation and poor outcome in chronic heart failure patients with mild left ventricular systolic dysfunction

Aims We aimed to evaluate the impact of glycometabolic imbalance as assessed by glycosylated haemoglobin [HbA(1c)] on neurohormonal activation and outcome in chronic heart failure (CHF). Methods and results Nine hundred and twenty CHF patients (65 ± 12 years, left ventricular ejection fraction 33 ± 10%, 29% diabetic patients) underwent a thorough humoral and clinical characterization, including HbA(1c), and were then followed up for the endpoint of cardiac death. In the whole population, diagnosis of diabetes resulted in no difference in neurohormonal or echocardiographic data, or in outcome. Conversely, the diabetic patients with HbA(1c) above 7% showed, in comparison to both diabetic patients with HbA(1c) below 7% and non-diabetic individuals, higher plasma renin activity (1.81, 0.48–5.68 vs. 1.23, 0.43–2.8 and 1.29, 0.44–5 ng/ml/h, respectively; P < 0.01 for both), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) (1602, 826–3498 vs. 1022, 500–3543 and 1134, 455–3545 ng/l, respectively; P < 0.01 for both) and worse symptoms with a higher rate of cardiac mortality vs. both diabetic patients with HbA1(c) below 7% and non-diabetic individuals (P < 0.05 for both). In the left ventricular ejection fraction 38–50% tertile (mild left ventricular dysfunction), elevated HbA(1c) was associated with higher NT-pro-BNP and PRA (P < 0.01), and, alongside NT-pro-BNP, resulted the only independent predictor of outcome beyond diagnosis of diabetes. HbA(1c) failed to show up differences in neuroendocrine activation or in outcome in moderate and severe left ventricular dysfunction tertiles. Conclusion Glycometabolic imbalance, as represented by HbA(1c), is associated with neurohormonal activation and poor prognosis in CHF patients, beyond diabetes. The impact of metabolic derangement on prognosis appears greater at the early stages of CHF, when it might exacerbate neurohormonal activation.

N-TERMINAL PRO-B-TYPE NATRIURETIC PEPTIDE VERSUS CLINICAL RISK SCORES FOR PROGNOSTIC STRATIFICATION IN HEART FAILURE PATIENTS

The estimation of the prognostic performance of the Seattle Heart Failure Model (SHFM) and Cardiac and Comorbid Conditions (3C-HF) scores, comparing it with a single assay of N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), leads to investigate if the adding of NT-proBNP to scores