The role of laboratory medicine in a value-based healthcare system: the example of heart failure patient management in the Italian context.

OBJECTIVE: As of today, healthcare systems worldwide face severe challenges that undermine their sustainability. The value-based healthcare (VBHC) approach has been proposed as a strategic and methodological framework to ensure the delivery of the best patient outcomes with economic efficiency. Through the illustrative example of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) for heart failure (HF) patient management in the context of the Italian National Healthcare system, this article explores the role that in vitro diagnostics (IVDs) can play in enabling value-based care models. SUBJECTS AND METHODS: 14 healthcare professionals representing the relevant professional figures involved in HF patient management met to revise the current HF patient journey and design a new care pathway that, leveraging on BNP/NT-proBNP, reflects the VBHC principles. RESULTS: The literature recognizes the dosage of BNP/NT-proBNP as the gold stan-dard for diagnosing HF. However, as of today, these IVDs are not employed at their full potential regarding HF patient management. A new patient journey is proposed so that patients are diagnosed early and properly monitored in the aftermath of hospitalization, improving outcomes at contained costs. CONCLUSIONS: As testified by the example of HF patient management in Italy, laboratory medicine can represent a lever for adopting value-based care models. Still, large-scale adoption of VBHC will call for structural reforms that revise how healthcare delivery is organized, measured, and reimbursed.

ADQI 7: the clinical management of the Cardio-Renal syndromes: work group statements from the 7th ADQI consensus conference.

Many patients with heart failure have underlying renal dysfunction, and similarly, patients with kidney failure are prone to cardiac failure. This has led to the concept of cardio-renal syndromes, which can be an acute or chronic cardio-renal syndrome, when cardiac failure causes deterioration in renal function, or acute and/or chronic Reno-Cardiac syndrome, when renal dysfunction leads to cardiac failure. Patients who develop these syndromes have increased risk of hospital admission and mortality. Although there are clinical guidelines for managing both heart failure and chronic kidney disease, there are no agreed guidelines for managing patients with cardio-renal and/or Reno-Cardiac syndromes, as these patients have typically been excluded from clinical trials. We have therefore reviewed the currently available published literature to outline a consensus of current best clinical practice for these patients.

Comparison between immunoradiometric and fluorimetric brain natriuretic peptide determination in patients with congestive heart failure.

UNLABELLED: This study compared two different methods, namely the immunoradiometric (IRMA) and fluorimetric (FIA), in order to determine plasma brain natriuretic peptide (BNP) in congestive heart failure (CHF) patients. METHODS: CHF in-patients underwent echocardiography and plasma BNP determination using both two methods. The echocardiograms analysed left ventricular end-systolic (LVESV) and end-diastolic (LVEDV) volumes and systolic dysfunction [left ventricular ejection fraction (LVEF) <50%]. RESULTS: Seventy-three (71% males, age 67 ± 9.6 yr) patients were enrolled, 31.5% affected by valvular heart disease. The mean LVEF was 39.8 ± 14.1%; in 26 (35%) a hypertensive etiology emerged. The immunoradiometric assay (IRMA) BNP was found to be significantly lower than the FIA determination 116.5 ± 149 pg/ml vs 267.3 ± 285.6 pg/ml; p=0.0001) and the two methods were closely correlated (r=0.89; p=0.00001). Logistic regression demonstrated a significant correlation between BNP, LVEF, and LVESV/LVEDV (r=-0.45, p=0.0003; r=-0.48, p=0.00001; r=0.22 p=0.003; r=0.34 p=0.0001; r=0.13 p=0.02; r=0.28 p=0.001 IRMA and FIA, respectively). IRMA BNP and FIA BNP significantly increased according to the worsening functional class [from 34.3 ± 60.2 pg/ml in NYHA (New York Heart Association) I to 555.5 ± 273.1 pg/ml in NYHA IV; from 86.1 ± 162.1 pg/ml in NYHA I to 1070 ± 42.2 pg/ml in NYHA IV, respectively]. In severe systolic dysfunction (LVEF<30%), receiver operating characteristic analysis revealed a satisfactorily sensitivity and specificity using a cut-off point of 50.6 pg/ml with IRMA and 243 pg/ml with FIA. In mild systolic dysfunction (LVEF<50%), a good sensitivity and specificity using a cut-off point of 42 pg/ml with IRMA and 182 pg/ml with FIA emerged. CONCLUSIONS: In CHF patients both BNP methods correlated with NYHA class, LVEF, and ventricular volumes.

Relationship between B-type natriuretic peptide levels and ventilatory response during cardiopulmonary exercise test in patients with chronic heart failure.

AIM: Aim of the study was to evaluate if brain natriuretic peptide (BNP) levels, a cardiac neurohormone well correlated with prognosis in chronic heart failure (CHF), are associated with enhanced ventilatory response to exercise, in ambulatory patients with intermediate peak oxygen uptake (PVO2). METHODS: Resting BNP was measured in 129 consecutive stable CHF patients with mild to moderate heart failure (90% New York Heart Association (NYHA) class II or III) and intermediate (10-18 mL/kg/min) PVO2, assessed during cardiopulmonary exercise test. Mean (SD) left ventricular ejection fraction (EF) and pulmonary systolic pressure (PAP) were 41 +/- 3% and 47 +/- 14 mmHg, respectively. The enhanced ventilatory response to exercise (EVR) was assessed as a slope of the relation between minute ventilation and carbon dioxide production (VE/VCO2 slope) > 35. RESULTS: Thirty-three over 129 patients (26%) had EVR. Mean BNP plasma level was 394 +/- 347 pg/mL. A significant correlation between BNP and EVR (r = 0.310; p < 0.01), was observed. In the logistic multivariate model, a BNP plasma level > 100 pg/mL had an independent predictive value for EVR (95% IC 1.68 to 10.5, Odds Ratio 4.23, p = 0.02). We found a significant correlation between BNP and PAP (r = 0.390; p < 0.001), and between PAP and EVR (r = 0.511; p < 0.01). CONCLUSIONS: In CHF patients with intermediate PVO2, plasma BNP is clearly related to the enhanced ventilatory response to exercise. In this subset, BNP levels could represent an effective alternative tool for the clinical assessment in patients with unreliable cardiopulmonary exercise test.

Coronary flow reserve of normal left anterior descending artery in patients with ischemic heart disease: A transesophageal Doppler study.

The aim of this study was to investigate the flow reserve of a normal left anterior descending coronary artery (LAD) in patients with coronary artery disease (CAD) of other epicardial vessels by Doppler transesophageal echocardiography (TEE). Thirty-one consecutive patients (age 59 +/- 8 years; 23 men) referred for TEE were considered. Eighteen patients had CAD and a 70% or greater LAD stenosis (group 1); 13 patients had right and/or circumflex CAD (>/=70% stenosis) and normal or minimally diseased LAD (group 2). Ten patients (age 54 +/- 11 years) with normal coronary arteries constituted group 3. Baseline and adenosine (0.160 microg/kg per minute intravenously over 60 minutes) flow velocities in the LAD were measured by pulsed Doppler examination during TEE. Peak and mean systolic and diastolic flow velocities were calculated. Adenosine/baseline peak and mean velocity ratios were used for evaluating blood flow reserve in the LAD. Heart rate and arterial pressure values were similar in the 3 groups at baseline and during adenosine infusion. Baseline and adenosine-related flow velocities were comparable in the 3 groups. Peak and mean diastolic velocity ratios were lower in groups 1 and 2 compared with group 3 (peak velocity ratio 1.68 +/- 0.81 and 1.93 +/- 0.35 vs 2.62 +/- 0.32, P <. 05; mean velocity ratio 1.71 +/- 0.86 and 2.01 +/- 0.41 vs 2.84 +/- 0.74, P <.05), whereas no differences were found between groups 1 and 2. No significant differences were found in systolic flow velocity ratios among the 3 groups. Patients with ischemic heart disease have a reduced diastolic flow velocity reserve in the LAD independent from the presence of significant LAD stenosis. Thus the adenosine TEE-Doppler study should be considered a screening test for CAD rather than for LAD disease.

Prognostic role of B-type natriuretic peptide in patients with diabetes and acute decompensated heart failure.

BACKGROUND: Several studies have reported the prognostic value of natriuretic peptides, but their predictive value in patients with diabetes mellitus is unknown. The aim of the study was to test the hypothesis that measurement of brain natriuretic peptide (BNP) levels in ambulatory patients with congestive heart failure (CHF) and diabetes can predict the occurrence of cardiovascular events at 6-month follow-up. METHODS: We enrolled 145 consecutive patient with diabetes [age 72 +/- 9 years, hypertension (21%), ischaemic heart disease (52%), atrial fibrillation (22%), preserved left ventricular function (29%)] seen in the outpatient heart failure clinic after an acute episode of cardiac failure. RESULTS: The median (25th/75th interquartile range) BNP concentrations at discharge were 186 (75-348) pg/ml. At 6-month clinical follow-up 10/145 (7%) subjects had died and 31/145 (21%) had been readmitted because of cardiac decompensation. BNP values of 200 and 500 pg/ml were found to have the best compromise between sensitivity (88 and 46%, respectively) and specificity (71 and 89%, respectively) for predicting events at 6 months. Multivariate Cox regression analysis identified only two parameters as predictors of events: serum creatinine [hazard ratio (HR) = 3.3; P = 0.02], and BNP plasma level BNP cut-off values (HR = 3.8; P = 0.03 for 201-499 pg/ml and HR = 7.7; P = 0.001 for > or = 500 pg/ml). CONCLUSION: These results suggest that BNP and serum creatinine are strong predictors of clinical events in patients with diabetes and CHF. In these patients, clinical outcome might be stratified by plasma BNP levels.

The BNP assay does not identify mild left ventricular diastolic dysfunction in asymptomatic diabetic patients.

AIMS: We examined the usefulness of BNP for screening for left ventricular (LV) diastolic dysfunction in a sample of type 2 diabetic patients, without structural heart disorder, who have never presented symptoms or signs of heart failure (HF). METHODS AND RESULTS: Seventy-six consecutive patients admitted to the Outpatient Diabetes Clinic were studied. Blood samples were analyzed using the Triage BNP fluorescence immunoassay (Biosite Diagnostics, La Jolla, CA, USA). Echocardiography examinations were performed, with no knowledge of the BNP value. A total of 39 patients out of 76 (51%) were diagnosed with LV diastolic dysfunction and 23 (30%) with LV hypertrophy. Of the patients with LV diastolic dysfunction, impaired relaxation and pseudonormal pattern accounted for 97 and 3% of the cases, respectively. BNP levels among subjects with LV diastolic dysfunction (26+/-22 pg/ml, n=39) were not significantly different from patients with normal LV function (24+/-23 pg/ml, n=37 pg/ml; Mann-Whitney U-test, Z=-0.4, n.s.). CONCLUSIONS: Our data confirm alarmingly high prevalence of LV diastolic dysfunction in asymptomatic individuals with diabetes. Identification of patients with preclinical diabetic cardiomyopathy should be a research and clinical priority. BNP levels cannot be used to detect mild LV diastolic dysfunction in this subset of patients, which requires Doppler echocardiography to be detected.

[Somatostatin and the cardiovascular system: experiences and prospective use]. / Somatostatina ed apparato cardiovascolare: esperienze e prospettive.

The recent demonstration that intravenous administration of somatostatin, an ubiquitous peptide-like substance, may interrupt paroxysmal supraventricular tachycardia in man has disclosed new perspectives in the assessment of the mechanisms of neuro-humoral cardiac regulation in normal and pathologic conditions. Prospective studies on normal subjects and diabetics with and without autonomic cardiac neuropathy, helped in giving an outlook on the mechanism by which somatostatin acts on the human heart. This substance exerts in vivo a powerful chronotropic and dromotropic influence on sinoatrial and A-V node cells both in normals and diabetics with and without autonomic cardiac neuropathy. This influence is blocked by preventive administration of atropine or atropine plus metoprolol (intrinsic heart rate). Since somatostatin-like-substances have been found in cholinergic postganglionic neurons of the cardiac vagus of some animals, the demonstrated "vagomimetic" action of somatostatin on human cardiac cells seems to support the hypothesis that also the human heart may contain vagal somatostatinergic neurons with modulatory function on the heart rate and rhythm. Present observations disclose new perspectives in the pathophysiology and therapy of cardiac arrhythmias.

ECG changes during dobutamine stress test and spontaneous recovery of contractility in patients with myocardial infarction.

UNLABELLED: Recent reports suggest a relationship between ECG changes and myocardial viability during dobutamine stress echocardiography in patients with myocardial infarction. The aim of the study was to analyze the predictive value of T-wave normalization and ST segment elevation during low- (10 mucg/Kg/m') and high-dose (40 mucg/Kg/m') dobutamine stress test for late spontaneous recovery of function in patients with a first uncomplicated Q-wave myocardial infarction. METHODS: Seventy eight consecutive patients (59 +/- 9 yrs; males = 67; anterior MI = 41, inferoposterior MI = 37 pts) underwent baseline 2D echo and dobutamine stress test at 9 +/- 2 days from onset of symptoms and they were free of cardiac events during the first three months after myocardial infarction. T-wave normalization (negative T-wave becoming > or = 1 mm upright in > or = 2 leads) and ST segment elevation (> or = 0.1 mm in > or = 2 leads) at low- and high-dose dobutamine infusion were compared with an improvement of contractility in the infarct area detected echocardiographically at three months. A wall motion score decrease in infarct area > or = 2 was the criterion for recovery of contractility. RESULTS: ST segment elevation occurred in 19/78 patients at low dose (24%) and in 45/78 patients at high dose (58%). Late recovery of contractility in the infarct area was observed in 38/78 patients (49%). The positive and negative predictive values of ST segment elevation for late recovery of contractility were, respectively, 63-56% at low dose and 47-48% at high dose. A baseline negative T-wave in > or = 2 leads was present in 56 patients, and 27 (48%) showed recovery of contractility at three months. T-wave normalization occurred in 14 patients at low-dose (25%) and in 29 patients at high-dose dobutamine infusion (52%). The positive and negative predictive values of T-wave normalization were, respectively, 71-59% at low dose and 62-67% at high dose. Both ECG markers were present in 10/56 patients at low dose and in 19 patients at high dose. The positive and negative predictive values, respectively, were 70-57% at low dose and 58-57% at high dose. At univariate analysis, neither the ECG changes alone nor their combination during dobutamine stress testing were shown to be significant predictors of recovery of function. CONCLUSIONS: Our study demonstrates that in patients with a first uncomplicated Q-wave myocardial infarction, the T-wave normalization and/or the ST segment elevation occurring during early dobutamine stress testing are not reliable predictors of late spontaneous recovery of contractility in the infarct area.

[Cardiac and metabolic investigations during 24 hour endurance skiing (Pinzolo, Italy)]. / Indagini cardiologiche e metaboliche nel corso di una 24 ore di sci da fondo (Pinzolo, Italia).

In the "24-hour Cross Country Ski Race of Pinzolo" skiers attempt to cover as long as possible distances within 24 hours. Cardiac and metabolic changes of 6 volunteer cross country skiers, aging 29 to 39 years, participating to the individual competition, were analysed. All skiers had negative clinical examination and resting standard 12-lead ECG, except for one who had a midsystolic click on auscultation suggesting the presence of mitral valve prolapse. They were submitted to 48-hour Holter monitoring (HM) going from 3:00 p.m. of the day before the race up to one hour after the end of competition. The period of HM going from 3 p.m. of the day before to 1.00 p.m. of the day of race (one hour before the start) was utilized as control as concerns arrhythmias, ST-T wave and QT interval changes observed during the period of competition. In all 6 skiers, standard 12-lead ECG was again recorded on completion of race. The following serum indexes were obtained in basal conditions and within one hour after the end of race: electrolytes (Na+, K+), Myoglobina (MG) and the enzymes GOT, GPT, LDH, CK and CK-MB. Complete urine analysis was also obtained before and immediately after the race. The distance covered by the skiers ranged from 189 to 260 Km, except for the skier with systolic click who covered 95.7 Km within 12 hour and then retired from the race for acute pain of knee.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of contractile reserve and inducible ischaemia on left ventricular remodelling after acute myocardial infarction.

OBJECTIVE: To assess the relative influence of contractile reserve and inducible ischaemia on subsequent left ventricular volume changes after myocardial infarction. DESIGN: Left ventricular end diastolic and end systolic index volumes were calculated prospectively at discharge and at six months in 143 patients referred for early postinfarction dobutamine stress echocardiography. On the basis of their responses to this test, patients were divided into three groups: scar (n = 48; group 1); contractile reserve (n = 36; group 2); inducible ischaemia (n = 59; group 3). RESULTS: At six months, the left ventricular end diastolic index volume decreased in group 2 (mean (SD), -3.9 (9.4) ml/m2) and increased in both group 1 (+2.8 (10.6) ml/m2, p = 0.009 v group 2) and group 3 (+7.5 (11.4) ml/m2, p < 0.0001 v group 2). The end systolic index volume decreased in group 2 (-4.9 (7.3) ml/m2) and increased in both group 1 (+1.3 (8.3) ml/m2, p = 0.0015 v group 2) and group 3 (+2.8 (8.9) ml/m2, p = 0.0002 v group 2). In multivariate analysis, the contractile reserve (hazard ratio 0.19, 95% confidence interval (CI) 0.14 to 0.47), inducible ischaemia (5.86, 95% CI 1.54 to 29.7), and end systolic index volume at discharge (1.04, 95% CI 0.99 to 1.11) were independent predictors of an increase in end diastolic index volume of > or = 15 ml/m2 at six months. CONCLUSIONS: Contractile reserve and inducible ischaemia, as detected by early dobutamine stress echocardiography, identify patients with differences in long term left ventricular remodelling after acute myocardial infarction.

Multicenter trial on prognostic value of inducible ischemia, assessed by dobutamine stress echocardiography and exercise electrocardiography test, in patients with uncomplicated myocardial infarction, treated with thrombolytic therapy.

BACKGROUND: Thrombolysis has reduced early and longterm mortality by about 20%; sometimes, however, there is a re-occlusion of the infarct related artery or an unsuccessful thrombolysis. In these situations, there is a possible increase in detrimental events in the follow-up. OBJECTIVES: The aim of the study was to compare the prognostic value of dobutamine echocardiography (DET) and ECG exercise test (EET) in pts submitted to thrombolysis. METHODS: One hundred and fifty-one pts, with acute uncomplicated myocardial infarction, were enrolled. The pts were able to perform EET and had a sufficient echocardiographic window; 58 had anterior myocardial infarction (38%), 79 had inferior (52%), 2 had lateral (1%), 12 had non-Q (8%). EET was performed with an initial load of 25 Watt, and thereafter, 25 W every two minutes. DET was performed with step-wise infusion every three minutes (5, 10, 20, 30 and 40 mcg/kg/min.). If the target heart rate was not reached, a further dose of 40 mcg/kg/min. together with atropine 0.25-1 mg was administered, in the absence of signs and symptoms of ischemia. RESULTS: During a mean (+/- SD) follow-up period of 8 +/- 4.5 months (range 1-23), 16 spontaneous events happened (4 deaths, 5 non-fatal re-infarctions, 7 unstable angina). One-hundred and three EET (68%) were negative for ongoing ischaemia, while 48 were positive, 79 DET (52%) were negative for ongoing ischaemia and 72 were positive (48%). Statistical results: DET and EET had a sensitivity of 41% and 54%, a specificity of 57% and 74%, a positive predictive value of 7% and 14%, a negative predictive value of 91% and 95%, an accuracy of 56% and 73%. Kaplan-Maier survival curves demonstrated that patients with Peak Wall motion > 1.8 and EET score > 3, had the higher risk of spontaneous events. CONCLUSION: A few spontaneous events happened in the follow-up. These data demonstrate that patients treated with thrombolysis are not at high risk of spontaneous events. DET and EET, therefore, have had a high negative predictive value. For this reason, we can conclude that pts with negative tests can be considered at low risk and do not need any further investigations.