Marina Parolini

Alcohol abuse and dilated cardiomyopathy in men

Excessive ethanol intake is reported in 3% to 40% of patients with idiopathic dilated cardiomyopathy (IDC). In the prevasodilator era, the prognosis was reportedly better in alcoholic than in IDC patients, an advantage limited to abstinent patients. No large series of patients systematically treated with angiotensin-converting enzyme inhibitors has since been described. We analyzed long-term outcome according to alcohol abuse in male patients with IDC. Among 338 men who had been prospectively enrolled in a multicenter registry, 79 (23%) were defined as alcohol abusers and further classified at follow-up as having stopped (AAS) or continued (AAC) abuse. AAC subjects at enrollment reported a higher daily alcohol intake than AAS subjects (178 +/- 113 vs 127 +/- 54 g/day, p = 0.012). During a mean of 59 +/- 35 months, 102 patients died and 45 underwent transplantation. Seven-year transplant-free survival was significantly lower in alcohol abusers (41%) than in patients with IDC (53%, p = 0.026), and significantly lower in AAC subjects (27%) than in either patients with IDC or AAS (45%) (p = 0. 018). Although IDC patients had beneficial changes in left ventricular function at follow-up, only AAS patients had significant improvement in ejection fraction. In this large series of patients treated with angiotensin-converting enzyme inhibitors and prospectively followed up, excessive alcohol intake was found in about one fourth of cases and persistent alcohol abuse correlated with a worse prognosis and function at follow-up.

Predictive value of EuroSCORE on long term outcome in cardiac surgery patients: a single institution study

Objectives: To assess the value of the European system for cardiac operative risk evaluation (EuroSCORE), a validated model for prediction of in-hospital mortality after cardiac surgery, in predicting long term event-free survival. Design and setting: Single institution observational cohort study. Patients: Adult patients (n  =  1230) who underwent cardiac surgery between January 2000 and August 2002. Results: Mean age was 65 (11) years and 32% were women. Type of surgery was isolated coronary artery bypass grafting in 62%, valve surgery in 23%, surgery on the thoracic aorta in 4%, and combined or other procedures in 11%. Mean EuroSCORE was 4.53 (3.16) (range 0–21); 366 were in the low (0–2), 442 in the medium (3–5), 288 in the high (6–8), and 134 in the very high risk group (⩾ 9). Information on deaths or events leading to hospital admission after the index discharge was obtained from the Regional Health Database. Out of hospital deaths were identified through the National Death Index. In-hospital 30 day mortality was 2.8% (n  =  34). During 2024 person-years of follow up, 44 of 1196 patients discharged alive (3.7%) died. By Cox multivariate analysis, EuroSCORE was the single best independent predictor of long term all cause mortality (hazard ratio (HR) 1.55, 95% confidence interval (CI) 1.03 to 2.34, p < 0.0001). In the time to first event analysis, 227 either died without previous events (n  =  20, 9%) or were admitted to hospital for an event (n  =  207, 91%). EuroSCORE (HR 1.60, 95% CI 1.36 to 1.89, p < 0.0001), the presence of ⩾ 2 co-morbidities versus one (HR 1.49, 95% CI 1.09 to 2.02, p < 0.0001), and > 96 hours’ stay in the intensive care unit after surgery (HR 2.04, 95% CI 1.42 to 2.95, p  =  0.0001) were independently associated with the combined end point of death or hospital admission after the index discharge. Conclusions: EuroSCORE and a prolonged intensive care stay after surgery are associated with long term event-free survival and can be used to tailor long term postoperative follow up and plan resource allocation for the cardiac surgical patient.

Early detection of cardiac dysfunction in thalassemic patients by radionuclide angiography and heart rate variability analysis

Abstract:  Background: Cardiac dysfunction remains the major cause of death in beta‐thalassemia. Aim of this study was to assess early myocardial damage in thalassemic patients with no symptoms or echocardiographic evidence of dysfunction at routine monitoring. Methods: Twenty patients (seven females; median 25 yr [first quartile 22,third quartile 28]) with beta‐thalassemia underwent radionuclide angiography (RNA) at rest and during low‐dose dobutamine infusion (5–10 γ/kg/min). Right and left ventricular ejection fractions (EF) were determined by first‐pass method and gated equilibrium acquisition, respectively. Twenty‐four‐hour Holter monitoring with time‐domain heart rate variability (HRV) assessment and echocardiographic follow‐up (21 months [5,27]) were performed. Results: Eleven patients showed regional wall motion abnormalities at RNA; left ventricular EF, HR and diastolic measurements significantly increased after dobutamine infusion. Patients with abnormal RNA right ventricular EF (n = 8, <0.45) showed lower echocardiographic left ventricular EF at the enrolment (0.54 [0.50,0.61] vs. 0.62 [0.56,0.67], P = 0.02) than those with a normal right ventricular EF. Patients with reduced standard deviation of the averages of RR intervals in all 5‐minute periods of entire recording (SDANN) (n = 6, <100 ms), a measure of HRV, had lower echocardiographic left ventricular EF (0.53 [0.49,0.62] vs. 0.62 [0.56,0.66], P = 0.03) and lower fractional shortening (0.28 [0.25,0.32] vs. 0.36 [0.30,0.39], P = 0.003) at the enrolment than those with normal SDANN. No significant association was found between RNA and HRV measurements and follow‐up left ventricular function. Conclusions: Right ventricular dysfunction and abnormal HRV may represent the early features of cardiac disease in thalassemic patients with no evidence of ventricular dysfunction at routine evaluation.

Early expression of pro- and anti-inflammatory cytokines in left ventricular assist device recipients with multiple organ failure syndrome.

To assess whether the combined evaluation of total Sequential Organ Failure Assessment (t-SOFA) score and pro- and anti-inflammatory cytokine profiles early after left ventricular assist device (LVAD) implant discriminates patients at high risk for multiple organ failure syndrome (MOFS) in the first month post-LVAD, we analyzed plasma interleukin (IL)-6, IL-8, IL-10, IL-1ra, IL-1&bgr;, tumor necrosis factor-&agr; (TNF-&agr;), and urine neopterin levels before (day 0) and at 4 hours, 1, 3, 7, 14, and 30 days after LVAD implant in 23 recipients. Eight patients died of MOFS between days 7 and 30 (nonsurvivors). At preimplant, only blood urea nitrogen and age were higher in nonsurvivors than survivors. At 4 hours, IL-8, IL-10, and IL1-ra levels were higher in nonsurvivors than in survivors; t-SOFA was also higher and peaked on day 3 in nonsurvivors. Only IL-8 levels on day 1 were significantly associated with a t-SOFA ≥10 on day 3 (odds ratio 1.10, 95% confidence interval 1.01–1.21, p = 0.04). Neopterin, marker of monocyte activation, increased significantly only in nonsurvivors (p < 0.001). These findings suggest that an activated inflammatory system soon after LVAD implant is implicated in MOFS development. Early monitoring of inflammatory mediators and t-SOFA score may be a valuable tool for outcome prediction in LVAD recipients.

Newborn screening of homocystinuria: quantitative analysis of total homocyst(e)ine on dried blood spot by liquid chromatography with fluorimetric detection

Identification of homocystinuric newborns is hindered by the pitfalls of neonatal screening programs. We propose a fluorimetric HPLC method with a rapid pre-analytical step for homocysteine determination from neonatal dried blood spot cards. Homocysteine in blood spots sampled among 2000 healthy newborns on living day 4, averaged 2.92+/-2.07 microM (range 0.4-7.5). In eight homocystinuric control children, mean values were 61.71+/-52.84 microM (range 18.9-145.7). The method showed a good linearity (r=0.999), precision (RSD<7%) and recovery (95%). The correlation between blood spots and plasma samples was r=0.90. This method has all the essential features for a homocystinuria screening program: an easy and rapid pre-analytical step combined with method linearity and precision.

Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance

This study investigates the impact of early left ventricular (LV)-mechanical unloading on systemic oxidative stress and inflammation in terminal heart failure patients and their impact both on multi organ failure and on intensive care unit (ICU) stay. Circulating levels of urinary 15-isoprostane-F(2t) (8-epi-PGF2(α)) and pro-inflammatory markers [plasma interleukin (IL)-6, IL-8, and urinary neopterin, a monocyte activation index] were analyzed in 20 healthy subjects, 22 stable end-stage heart failure (ESHF) patients and in 23 LV assist device (LVAD) recipients at pre-implant and during first post-LVAD (PL) month. Multi-organ function was evaluated by total Sequential Organ Failure Assessment (tSOFA) score. In LVAD recipients the levels of oxidative-inflammatory markers and tSOFA score were higher compared to other groups. After device implantation 8-epi-PGF2(α) levels were unchanged, while IL-6, and IL-8 levels increased during first week, and at 1month returned to pre-implant values, while neopterin levels increased progressively during LVAD support. The tSOFA score worsened at 1 PL-week with respect to pre-implant value, but improved at 1 PL-month. The tSOFA score related with IL-6 and IL-8 levels, while length of ICU stay related with pre-implant IL-6 levels. These data suggest that hemodynamic instability in terminal HF is associated to worsening of systemic inflammatory and oxidative milieu that do not improve in the early phase of hemodynamic recovery and LV-unloading by LVAD, affecting multi-organ function and length of ICU stay. This data stimulate to evaluate the impact of inflammatory signals on long-term outcome of mechanical circulatory support.

Association of pre-operative interleukin-6 levels with Interagency Registry for Mechanically Assisted Circulatory Support profiles and intensive care unit stay in left ventricular assist device patients

BACKGROUND Inflammatory mechanisms are associated with worse prognosis in end-stage heart failure (ESHF) patients who require left ventricular assist device (LVAD) support. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles describe patient condition at pre-implant and outcome. This study assessed the relationship among inflammation patterns and INTERMACS profiles in LVAD recipients. METHOD Thirty ESHF patients undergoing LVAD implantation as bridge to transplant were enrolled. Blood and urine samples were collected pre-operatively and serially up to 2 weeks post-operatively for assessment of inflammatory markers (plasma levels of interleukin [IL]-6, IL-8, IL-10, and osteopontin, a cardiac inflammatory-remodeling marker; and the urine neopterin/creatinine ratio, a monocyte activation marker). Multiorgan function was evaluated by the total sequential organ failure assessment (tSOFA) score. Outcomes of interest were early survival, post-LVAD tSOFA score, and intensive care unit (ICU) length of stay. RESULTS Fifteen patients had INTERMACS profiles 1 or 2 (Group A), and 15 had profiles 3 or 4 (Group B). At pre-implant, only IL-6 levels and the IL-6/IL-10 ratio were higher in Group A vs B. After LVAD implantation, neopterin/creatinine ratio and IL-8 levels increased more in Group A vs B. Osteopontin levels increased significantly only in Group B. The tSOFA score at 2 weeks post-LVAD and ICU duration were related with pre-implant IL-6 levels. CONCLUSIONS The INTERMACS profiles reflect the severity of the pre-operative inflammatory activation and the post-implant inflammatory response, affecting post-operative tSOFA score and ICU stay. Therefore, inflammation may contribute to poor outcome in patients with severe INTERMACS profile.

Plasma Total Cysteine and Cardiovascular Risk Burden: Action and Interaction

We hypothesized that redox analysis could provide sensitive markers of the oxidative pathway associated to the presence of an increasing number of cardiovascular risk factors (RFs), independently of type. We classified 304 subjects without cardiovascular disease into 4 groups according to the total number of RFs (smoking, hypertension, hypercholesterolaemia, hyperhomocysteinaemia, diabetes, obesity, and their combination). Oxidative stress was evaluated by measuring plasma total and reduced homocysteine, cysteine (Cys), glutathione, cysteinylglycine, blood reduced glutathione, and malondialdehyde. Twenty-seven percent of subjects were in group 0 RF, 26% in 1 RF, 31% in 2 RF, and 16% in ≥3 RF. By multivariable ordinal regression analysis, plasma total Cys was associated to a higher number of RF (OR = 1.068; 95% CI = 1.027–1.110, P = 0.002). Total RF burden is associated with increased total Cys levels. These findings support a prooxidant effect of Cys in conjunction with RF burden, and shed light on the pathophysiologic role of redox state unbalance in preclinical atherosclerosis.

Long term survival effect of metoprolol in dilated cardiomyopathy

Objective To evaluate the additive effect of metoprolol treatment on long term incidence of fatal and non-fatal cardiac events in idiopathic dilated cardiomyopathy. Design 586 patients with idiopathic dilated cardiomyopathy were prospectively enrolled in a multicentre registry and followed up for a mean (SD) of 52 (32) months. Metoprolol, carefully titrated to the maximum tolerated dose, was added to conventional heart failure treatment in 175 patients. Results Survival and transplant-free survival at seven years were significantly higher in the 175 metoprolol treated patients than in the remaining 411 on standard treatment (81%v 60%, p < 0.001, and 69% v 49%, p < 0.001, respectively). By multivariate analysis, metoprolol independently predicted survival and transplant-free survival (relative risk reduction values for all cause mortality and combined mortality or transplantation 51% (95% confidence interval 21% to 69%), p = 0.002, and 34% (5% to 53%), p = 0.01, respectively). New York Heart Association class, left ventricular end diastolic diameter, and pulmonary wedge pressure were also predictive. Seven year survival (80% v 62%, p = 0.004) and transplant-free survival (68% v 51%, p = 0.005) were significantly higher in 127 metoprolol treated cases than in 127 controls selected from the entire control cohort and appropriately matched. Metoprolol was associated with a 30% reduction in all cause mortality (7% to 48%, p = 0.015) and a 26% reduction in mortality or transplantation (7% to 41%, p = 0.009). Conclusions—The addition of metoprolol to standard heart failure treatment, including angiotensin converting enzyme inhibitors, was effective in the long term, reducing both all cause mortality and transplantation in patients with idiopathic dilated cardiomyopathy.

Plasma glutathione levels are independently associated with γ-glutamyltransferase activity in subjects with cardiovascular risk factors

To investigate whether GGT (γ-glutamyltransferase) is associated to specific redox patterns. GGT, total and reduced aminothiols and malondialdehyde, were measured in 150 subjects (83 males, 48 (39–56) years), with none, one or more risk factors. By univariable analysis GGT was positively associated with age (p =0.001), male gender (p <0.001), risk factor number (p <0.001), ACE-inhibitors (p =0.008), anti-platelet agents (p =0.029), atherothrombotic events (p =0.001), glucose (p =0.013), malondialdehyde (p =0.029), plasma total cysteine (p =0.046) and inversely associated with plasma total glutathione (p =0.001). By multivariable analysis only male gender (p <0.001), risk factor number (p <0.001) and glutathione (p <0.001) were independently associated with GGT activity. These findings suggest that an ongoing redox imbalance, in terms of decreased plasma glutathione, is associated with raised GGT activity in subjects with a greater risk factor burden.