Lorenzo Franceschini

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.

Aortic Distensibility Independently Affects Exercise Tolerance in Patients With Dilated Cardiomyopathy

Background—Peak exercise oxygen consumption (&OV0312;o2) is crucial for the prognostic stratification of patients with congestive heart failure, but its hemodynamic determinants are still not completely understood. Aortic wall elasticity modulates left ventricular function and coronary blood flow. Whether an increased aortic pulse-wave velocity (PWV), a known marker of arterial stiffness, may predict peak &OV0312;o2 in patients with dilated cardiomyopathy (DCM) has to be clarified. Methods and Results—A total of 78 patients with clinical diagnosis of DCM (aged 62±11 years; female 29%; mean ejection fraction 34±9%) were selected. All patients underwent a complete echocardiographic-Doppler evaluation. Aortic PWV was measured by Doppler ultrasonography immediately before the exercise. A bicycle exercise test with expiratory gas exchange monitoring was performed to determine &OV0312;o2. Plasma concentration of the amino-terminal propeptide of type III procollagen (PIIINP), a marker of extracellular matrix turnover, was determined. Mean PWV was 5.7±2.2 m/s, and &OV0312;o2 was 16.5±4.5 mL · kg−1 · min−1. The hemodynamic variables correlated with &OV0312;o2 were PWV (r =−0.39, P =0.0007) and stroke volume (r =0.38, P =0.002). In a multivariate analysis, PWV (P =0.04) and stroke volume (P =0.05) were independently correlated with &OV0312;o2, accounting for 34% of its variance. PIIINP levels correlated with PWV (r =0.35, P =0.002) and a more restrictive diastolic filling pattern (r =0.40, P =0.02). Conclusions—Increased aortic stiffness measured by PWV is an independent predictor of peak &OV0312;o2 and could partially explain exercise intolerance in patients with DCM.

Amino-terminal propeptide of type III procollagen is associated with restrictive mitral filling pattern in patients with dilated cardiomyopathy: a possible link between diastolic dysfunction and prognosis

Objective: To analyse the relation between restrictive mitral pattern, amino-terminal propeptide of type III procollagen (PIIINP), and prognosis in patients with dilated cardiomyopathy. Design: Prospective cohort study of 106 patients with dilated cardiomyopathy. Setting: Tertiary care centre. Main outcome measures: PIIINP concentration, echocardiographic variables, oxygen consumption, hospitalisation for heart failure, and cardiac mortality were evaluated in patients grouped by the presence of non-restrictive (group 1), reversible (group 2), and irreversible restrictive mitral pattern (group 3). Results: Groups differed regarding left ventricular ejection fraction (group 1, mean (SD) 36 (6)%, group 2, 29 (8)%, group 3, 25 (6)%; p  =  0.0001), left atrial ejection fraction (group 1, 0.47 (0.1)%, group 2, 0.43 (0.2)%, group 3, 0.26 (0.1)%; p < 0.0001), and PIIINP (p  =  0.001). Multivariate analysis showed that PIIINP was related to mitral pattern (odds ratio 0.8, 95% confidence interval 0.23 to 1.4, p  =  0.006) independently of left atrial and ventricular ejection fractions. After 21 months, survival was 88% and 34% (p  =  0.0001) in patients with non-restrictive and irreversible restrictive mitral patterns, respectively. Conclusion: In patients with dilated cardiomyopathy, restrictive mitral pattern is associated with higher PIIINP and worse prognosis.

Left Atrial Volume Provides Independent and Incremental Information Compared With Exercise Tolerance Parameters in Patients With Heart Failure and Left Ventricular Systolic Dysfunction

Objective: Left atrial volume (LAV) is a powerful predictor of outcome in patients with chronic heart failure (CHF) independently of symptomatic status, age and left ventricular (LV) function. It is unknown whether LAV provides independent and incremental information compared with exercise tolerance parameters. Methods: 273 patients with CHF (mean (SD) 62 (9) years; 13% female) prospectively underwent echocardiography and exercise testing with maximal oxygen consumption (Vo2). The primary end point was composite and included cardiac death, hospitalisation for worsening heart failure or cardiac transplantation. Results: At Cox proportional hazard analysis, LAV normalised for body surface area (LAV/BSA) was strongly associated with mortality (hazard ratio (HR) = 1.027 (95% CI 1.018 to 1.04), p<0.001). The predictive value of LAV/BSA was independent of Vo2 and LV ejection fraction (EF) (HR = 1.014 (1.002 to 1.025), p = 0.02; HR = 0.95 (0.91 to 0.99), p = 0.02; HR = 0.89 (0.82 to 0.98), p = 0.02 for LAV/BSA, EF and Vo2, respectively). Receiver operator characteristic (ROC) curve analysis identified the best cut-off values for prediction of the end point. LAV/BSA >63 ml, EF <30% and Vo2 <16 ml/kg/min were considered to be risk factors. Patients with three risk factors had an HR of 38 (95% CI 11 to 129) compared with patients with no risk factors. Conclusion: LAV provides powerful prognostic information incrementally and independently of Vo2. LAV, EF and Vo2 can be used to build a risk prediction model, which can be used clinically.

Nonalcoholic fatty liver disease is associated with ventricular arrhythmias in patients with type 2 diabetes referred for clinically indicated 24-hour holter monitoring

OBJECTIVE Recent studies have suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of heart rate–corrected QT interval prolongation and atrial fibrillation in patients with type 2 diabetes. Currently, no data exist regarding the relationship between NAFLD and ventricular arrhythmias in this patient population. RESEARCH DESIGN AND METHODS We retrospectively analyzed the data of 330 outpatients with type 2 diabetes without preexisting atrial fibrillation, end-stage renal disease, or known liver diseases who had undergone 24-h Holter monitoring for clinical reasons between 2013 and 2015. Ventricular arrhythmias were defined as the presence of nonsustained ventricular tachycardia (VT), >30 premature ventricular complexes (PVCs) per hour, or both. NAFLD was diagnosed by ultrasonography. RESULTS Compared with patients without NAFLD, those with NAFLD (n = 238, 72%) had a significantly higher prevalence of >30 PVCs/h (19.3% vs. 6.5%, P < 0.005), nonsustained VT (14.7% vs. 4.3%, P < 0.005), or both (27.3% vs. 9.8%, P < 0.001). NAFLD was associated with a 3.5-fold increased risk of ventricular arrhythmias (unadjusted odds ratio [OR] 3.47 [95% CI 1.65–7.30], P < 0.001). This association remained significant even after adjusting for age, sex, BMI, smoking, hypertension, ischemic heart disease, valvular heart disease, chronic kidney disease, chronic obstructive pulmonary disease, serum γ-glutamyltransferase levels, medication use, and left ventricular ejection fraction (adjusted OR 3.01 [95% CI 1.26–7.17], P = 0.013). CONCLUSIONS This is the first observational study to show that NAFLD is independently associated with an increased risk of prevalent ventricular arrhythmias in patients with type 2 diabetes.

Mitral and aortic valve sclerosis/calcification and carotid atherosclerosis: results from 1065 patients

This study assesses whether aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are associated with carotid artery atherosclerosis, independently of traditional cardiovascular risk factors. A total of 1065 patients underwent both echocardiography and carotid artery ultrasound scanning. AVS and MAC were defined as focal areas of increased echogenicity and thickening of the aortic leaflets or mitral valve annulus. Carotid artery atherosclerosis was defined as presence/absence of any atherosclerotic plaque or presence/absence of plaque >50 %. Of 1065 patients (65 ± 9 years; 38 % female) who comprised the study population, 642 (60 %) had at least one atherosclerotic plaque. AVS, but not mitral valve sclerosis; was associated with the presence of carotid atherosclerosis (odds ratio (OR) 1.9, 95 % confidence interval (CI) 1.2–3.9; P = 0.005) and the degree of carotid atherosclerosis (OR 2.1, 95 % CI 1.2–3.9; P = 0.01) in a multivariate model including age, gender, previous ischemic heart disease, hypertension, dyslipidemia, smoking, diabetes, family cardiovascular history, left ventricular size, mass, and ejection fraction, and left atrial size. AVS is a significant predictor of carotid atherosclerosis, independently of other cardiovascular clinical and echocardiographic risk factors.

Usefulness of ultrasonographic markers of carotid atherosclerosis (intima-media thickness, unstable carotid plaques and severe carotid stenosis) for predicting presence and extent of coronary artery disease.

Objective To investigate the usefulness of carotid ultrasound evaluation in predicting the presence and the extent of coronary artery disease in a consecutive series of patients. Design We examined retrospectively 1337 patients in whom both coronary angiography and carotid ultrasound were evaluated, from 1995 to 2005. Markers of carotid artery disease were considered, such as intima–media thickness more than 0.90 mm, unstable plaque and severe stenosis (≥70%). Carotid risk score was defined as the sum of these parameters. We considered as affected by significant coronary artery disease those patients with at least one lesion more than 50% within the main branches of the coronary arteries. Results The markers of carotid atherosclerosis increased proportionally in patients with one-, two- or three-vessel coronary artery disease. At univariate analysis, intima–media thickness more than 0.90 mm was associated with an odds ratio of coronary artery disease of 2.28 (1.8–2.9) (P < 0.0001), unstable plaque 3.6 (2.3–5.7) (P < 0.001) and severe carotid stenosis 4.2 (2.0–8.7) (P = 0.0001). At multivariate analysis, the three markers mentioned above were independent risk factors for coronary artery disease even when considering other risk factors. Conclusion We confirmed the usefulness of carotid ultrasound evaluation in predicting the presence and extent of coronary artery disease. Considering the high correlation between carotid and coronary artery disease, carotid screening is useful in patients with coronary artery disease. In patients with an occasional finding of a carotid risk score of at least 2, a careful search for coronary artery disease seems warranted.

Usefulness of transesophageal atrial pacing combined with two-dimensional echocardiography (echo-pacing) in predicting the presence and site of residual jeopardized myocardium after uncomplicated acute myocardial infarction

The usefulness of transesophageal atrial pacing combined with 2-dimensional echocardiography (echo-pacing) in predicting the presence and site of jeopardized myocardium, defined as areas of myocardium perfused by a vessel with a stenosis > or = 75% or by a collateral circulation if the supplying vessel was occluded, was evaluated in 31 patients with uncomplicated acute myocardial infarction who underwent coronary angiography. All 5 patients without jeopardized myocardium had a negative test, whereas 24 of 26 with jeopardized muscle had a positive test (sensitivity 92%; specificity 100%). To identify the site of jeopardized myocardium, tests that were positive for development of new asynergies were analyzed further, distinguishing those positive in the infarct or remote zone. Seven of 8 patients with new asynergies in the remote zone had areas of jeopardized myocardium outside the territory of distribution of the infarct-related vessel, whereas only 2 of 12 with new asynergies in the infarct zone had areas of jeopardized myocardium outside that territory (p < 0.01), correctly predicting the site of jeopardized myocardium in 17 of 20 cases. In conclusion, echo-pacing is useful for detecting the presence and site of jeopardized myocardium after an acute myocardial infarction.

Antihypertensive effect of lisinopril assessed by 24-hour ambulatory monitoring: a double-blind, placebo-controlled, cross-over study.

Summary: The antihypertensive effect of the angiotensin-converting enzyme (ACE) inhibitor lisinopril administered in a single dose of 20 mg was evaluated by ambulatory blood pressure monitoring (ABPM) in a double-blind, placebo-controlled, cross-over study. Twenty-four patients (21 men and 3 women, mean age 52 ± 6 years) with mild to moderate hypertension were included in the study and randomly assigned to two consecutive treatments with lisinopril 20 mg and placebo, each administered for 4 weeks. On the last day of each treatment, BP was assessed by noninvasive 24-h ABPM. BP was significantly lower after lisinopril than after placebo in a 24-h period (mean 24-h systolic BP (SBP) with lisinopril 120 ± 7 mm Hg and with placebo 135 ± 9 mm Hg; mean day SBP with lisinopril 125 ± 3 mm Hg and with placebo 142 ± 5 mm Hg; mean night SBP with lisinopril 112 ± 4 mm Hg and with placebo 124 ± 6 mm Hg; mean 24-h diastolic BP (DBP) with lisinopril 76 ± 6 mm Hg, and with placebo 87 ± 8 mm Hg; mean day DBP with lisinopril 80 ± 3 mm Hg and with placebo 93 ± 4 mm Hg; mean night DBP with lisinopril 69 ± 2 mm Hg and with placebo 79 ± 5 mm Hg, p < 0.001). Mean 24-h, mean day, and mean night heart rate (HR) did not differ significantly between placebo and lisinopril treatments. Repeated-measures analysis of variance (ANOVA) showed a significant influence on SBP (p 0.001) and DBP (p < 0.001) throughout the treatment. A significant time effect was also evident both for SBP (p 0.001) and DBP (p < 0.001). The interaction of time and treatment was not significant, suggesting that the circadian rhythm of BP was not different during the two treatments. No serious side effects were observed during this study.