Gianantonio Nappi

LOWERing the INtensity of oral anticoaGulant Therapy in patients with bileaflet mechanical aortic valve replacement: Results from the “LOWERING-IT” Trial

BACKGROUND Moderate anticoagulation after mechanical heart valve replacement has been proposed to reduce the risk of bleeding related to lifelong anticoagulation. However, the efficacy of such reduced antithrombotic regimens is still unknown. The present prospective open-label, single-center, randomized controlled trial aimed to evaluate the safety and feasibility of reduced oral anticoagulation after isolated mechanical aortic valve replacement. METHODS Low-risk patients undergoing bileaflet mechanical aortic valve replacement were randomized to a low International normalized ratio (INR) target (1.5-2.5; LOW-INR group) or to the standard currently recommended INR (2.0-3.0; CONVENTIONAL-INR group) through daily coumarine oral therapy. No aspirin was added. Median follow-up was 5.6 years. The primary outcome was assessment of noninferiority of the low over the standard anticoagulation regimen on thromboembolic events. Secondary end point was the superiority of the reduced INR target strategy on bleeding events. RESULTS We analyzed 396 patients (197 in the LOW-INR group and 199 in the CONVENTIONAL-INR group). The mean of INR was 1.94 +/- 0.21 and 2.61 +/- 0.25 in the LOW-INR and CONVENTIONAL-INR groups, respectively (P < .001). One versus three thromboembolic events occurred in the LOW-INR and CONVENTIONAL-INR, respectively, meeting the noninferiority criterion (P = .62). Total hemorrhagic events occurred in 6 patients in the LOW-INR group and in 16 patients in the CONVENTIONAL-INR group (P = .04). CONCLUSIONS LOWERING-IT trial established that the proposed LOW-INR target is safe and feasible in low-risk patients after bileaflet aortic mechanical valve replacement. It results in similar thrombotic events and in a significant reduction of bleeding occurrence when compared to the conventional anticoagulation regimen.

Mechanical Aortic Valve Replacement in Young Women Planning on Pregnancy : Maternal and Fetal Outcomes Under Low Oral Anticoagulation, a Pilot Observational Study on a Comprehensive Pre-Operative Counseling Protocol

OBJECTIVES This pilot prospective observational study aimed to evaluate the maternal and fetal outcomes of pregnancies under low-dose oral anticoagulation therapy after aortic mechanical replacement. BACKGROUND Need for valve replacement is still an issue for young women with native valve disease who are planning on future pregnancy. Choice of replacement device is a challenging clinical task. METHODS A comprehensive pre-operative counseling protocol to guide choice of replacement device was developed. The pre-operative anticoagulation trial to determine the warfarin daily dosage needed to reach target international normalized ratio (INR) represented the main stem of such protocol. Pregnancies on low-dose anticoagulation therapy (target INR: 1.5 to 2.5) were allowed in a highly selected subset of mechanical aortic valve recipients. RESULTS Twenty-two patients of 40 originally referred for native valve disease surgery requiring valve replacement, safely underwent the pre-operative anticoagulation challenge. No maternal or fetal complications were detected in 16 pregnancies under low oral anticoagulation. Patterns of warfarin daily dosage and induced INRs were characterized during pregnancy. CONCLUSIONS In this small sample observational study, a pre-operative anticoagulation therapy trial helped young women scheduled for valve replacement to acquire complete information as to the choice of prosthetic device. In selected third-generation mechanical aortic prosthesis recipients, low-dose anticoagulation therapy seems safe and feasible for both mother and fetus. Further studies are needed to validate this approach.

Surgical treatment of bicuspid aortic valve disease: Knowledge gaps and research perspectives

Supplemental material is available online.Sempre la praticadeveessereedificata sopra la bonateorica. [Practice must always be founded on soundtheory.]—Leonardo Da Vinci (1452-1519; providedthe firstdepiction of abicuspid aorticvalve).Research on bicuspid aortic valves (BAV) and associatedconditions is increasing exponentially. A major part of thecurrent knowledge on BAV is derived from investigationscarried out in the clinical setting, especially the surgicalsetting, as a consequence of the epidemiologic and surgicalimportance of its valvular and vascular complications. Forexample, most of the stenotic valves explanted at the timeof aortic valve replacement are congenitally malformed.

The Need for a Specific Risk Prediction System in Native Valve Infective Endocarditis Surgery

The need for a specific risk score system for infective endocarditis (IE) surgery has been previously claimed. In a single-center pilot study, preliminary to future multicentric development and validation, bivariate and multivariate (logistic regression) analysis of early postoperative mortality predictors in 440 native valve IE patients were performed. Mathematical procedures assigned scores to the independent predictors emerged (AUC of the ROC curve: 0.88). Overall mortality was 9.1%. Six predictors were identified and assigned scores, including age (5–13 points), renal failure (5), NYHA class IV (9), critical preoperative state (11), lack of preoperative attainment of blood culture negativity (5), perivalvular involvement (5). Four risk classes were drawn ranging from “very low risk” (≤5 points, mean predicted mortality 1%), and to “very high risk” (≥20 points, 43% mortality). IE-specific risk stratification models are both needed, as disease-specific factors (e.g., cultures, abscess), beside the generic ones (e.g., age, renal impairment) affect mortality, and feasible.

Leukoreduction program for red blood cell transfusions in coronary surgery: Association with reduced acute kidney injury and in-hospital mortality

OBJECTIVE Leukocytes in allogeneic blood transfusions cause several immunomodulatory events. This before-and-after cohort study evaluated clinical outcomes after adoption of prestorage leukoreduction program for blood transfusions, with particular focus on acute kidney injury. METHODS One thousand thirty-four consecutive patients who underwent on-pump coronary artery bypass grafting between January 2004 and December 2007 were included. Propensity score analysis for transfusion was performed in the whole population; patients who were actually transfused were then divided according to leukoreduction. From these 2 groups, 147 pairs matched for propensity score were considered to evaluate with bivariate and multivariable analyses the effects of leukoreduction, with all-cause in-hospital mortality and morbidity as main outcomes. RESULTS Unadjusted in-hospital mortalities were 6.6% for the entire cohort and 44.2% for those with acute kidney injury. In the matched population, after introduction of leukoreduction, mortality rates decreased to 5.4% (vs 11.4%) and acute kidney injury (RIFLE [Risk, Injury, Failure, Loss of function, End-stage renal disease] class R or greater) dropped from 51.7% to 41.5% (relative risk -20%, P < .045). No difference emerged regarding other major complications. At multivariable analysis, intra-aortic balloon pump, RIFLE score, and propensity score for transfusion proved independent predictors of in-hospital mortality. Intra-aortic balloon pump and nonleukodepleted transfusion emerged as independent predictors of acute kidney injury. Multivariable analysis on the overall cohort of transfused patients confirmed that nonleukodepleted transfusion was an independent predictor of acute kidney injury. CONCLUSIONS Leukoreduction of allogeneic blood products is associated with decreased acute kidney injury and mortality in highly transfused patients.

Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation

OBJECTIVES Bicuspid aortic valve (BAV)-related aortopathy is increasingly recognized to be a heterogeneous disease entity, although the surgical approach, from indications to techniques, is still standard rather than individualized. We aimed to define the determinants of aortic dilatation in BAV patients stratified according to the valve morphotype. METHODS A consecutive echocardiographic series of 622 BAV patients was analysed. Among demographic (age, sex), anthropometric (height, weight, body surface area, body mass index), clinical (associated diseases) and echocardiographic variables (valve function, ventricular parameters), the determinants of aortic root and ascending tract diameter were assessed by multivariate regression models, as well as the predictors of aortic dilatation (size index >2.1 cm/m(2)) both in the overall population and separately in groups of different valve morphotypes (RL, right-left fusion; RN, right-non-coronary fusion). RESULTS Independent determinants of aortic root diameter (at sinuses) were age (P < 0.001), significant aortic regurgitation (P < 0.001), sex (female protective, P < 0.001) and valve morphotype (RN protective, P < 0.001). Independent determinants of ascending aortic diameter (tubular tract) were age (P < 0.001), RN morphotype (P < 0.001), body mass index (P = 0.005) and chronic obstructive pulmonary disease (P < 0.001). In univariate analysis, the RL morphotype was associated with dilatation (ASI > 2.1 cm/m(2)) at sinuses in 41% cases vs 22% for RN (P < 0.001), and the RN morphotype was associated with dilatation at the tubular tract in 68 vs 56% for RL (P = 0.007). The presence of root dilatation was predicted by age and absence of significant stenosis in the RL morphotype subgroup, and by severe regurgitation in the RN subgroup. In the RL-type subgroup, non-regurgitant aortic valve and chronic lung disease predicted dilatation at the ascending level; and in the RN-type subgroup, age and obesity. CONCLUSIONS The two most common BAV morphotypes are associated with aortic dilatation at two different tracts (RL at the root; RN at the tubular ascending tract) independently of valve function. Moreover, the determinants of aortic dilatation were at least in part different between the two morphotypes: this may provide stratification criteria for individualized methods of follow-up and treatment.

Ascending aorta dilatation in aortic valve disease: morphological analysis of medial changes

We investigated whether and how the severity of medial degeneration lesions varies along the circumference of the dilated intrapericardial aorta. Two groups of aortic wall specimens, respectively harvested in the convexity and concavity of ascending aorta in 72 patients undergoing surgery for dilatation of the intrapericardial aorta associated with aortic valve disease, were separately sent for pathology, morphometry, and ultrastructural examination. Cystic medial necrosis, fibrosis, and elastic fiber fragmentation were classified into three degrees of severity; their mean degree and morphometric findings in the convexity and in the concavity specimens were compared by paired t-test. Correlation between echocardiographic degree of aortic dilatation and severity of medial degeneration was assessed separately for each of the two groups of specimens. Morphologically, medial degeneration was found in all cases; a higher mean degree was found in the convexity group (2.39 ± 0.58 vs 1.44 ± 0.65 in the concavity group; P < 0.001). At morphometry normal smooth muscle cells in the convexity specimens were significantly reduced (P = 0.007); the length (P = 0.012) and number (P = 0.009) of elastic fibers reduced and increased, respectively. Moreover, in the convexity specimens a significantly smaller amount of smooth muscle cells and an increase of immunohistochemical labeling of apoptosis-associated proteins in the subintimal layer of the media was noticed. Correlation between aortic ratio and medial degeneration degree was significant in the convexity group (P < 0.001), but not in the concavity group (P = 0.249). Scanning electron microscopy analysis confirmed morphological results and allowed us to better distinguish the early pathological cavities from the microvessels, which were in the outer media in normal aorta and ubiquitous in aortitis or atherosclerosis. Electron transmission microscopy analysis showed changes in the extracellular matrix and smooth muscle cells, and these changes increased from the intima to the adventitial layer of the media. In dilated intrapericardial aorta, medial degeneration changes and expression of apoptosis-associated proteins are more marked in the ascending aorta convexity, likely due to hemodynamic stress asymmetry. Ultrastructural findings allow us to distinguish the early medial changes not yet evident on light microscopy.

Implications of acute kidney injury after heart transplantation: what a surgeon should know

OBJECTIVE Data regarding risks and consequences of acute kidney injury (AKI) after cardiac transplantation are dismissingly few and unclear. This study defined the incidence, risk factors and prognostic implication of AKI in a single-center cohort operated on between January 1999 and December 2008. METHODS Data from 307 consecutive recipients (mean age: 47.42 ± 13.58, 20.5% female, 18.9% diabetics, 19.5% with previous cardiac operations, 26.4% hospitalized, 78.4 ± 33.7 ml min(-1) preoperative glomerular filtration rate (eGFR)) were analyzed using multivariable logistic regression modeling. AKI was defined according to RIFLE (Risk, Injury, and Failure; and Loss, and End-stage kidney disease) criteria. RESULTS RIFLE scores of I or F were detected in 14%, and continuous venovenous hemofiltration was needed in 6.1%. Risk factors for AKI were: previous cardiac operation (odds ratio (OR) 2.35; 95% confidence interval (CI), 1.11-4.9), blood transfusion (OR 1.08; 95% CI, 1.011-1.16), troponin I release >10 (OR 1.031; 95% CI, 1.001-1.064), length of ischemic time (OR 1.008; 95% CI, 1.011-1.16). Overall hospital mortality averaged 7.8% and overall 1-year mortality was 10.4%; both mortality rates increased with each RIFLE stratification (Normal 3.4%, RIFLE R = 7.1%; RIFLE I = 25.7%; and RIFLE F = 37.5% and Normal 5.6%, RIFLE R = 11.8%, RIFLE I = 25.7%, and RIFLE F = 37.5%, respectively). AKI proved independent predictors of both early and 1-year mortality. The burden of AKI significantly affected 1-year kidney function (Δ preoperative GFR-1-year GFR in AKI vs no AKI = -25.872 ± 22.54 vs -7.968 ± 34.18, p = 0.015). CONCLUSIONS AKI is a highly prevalent and prognostically important complication. Some of the risk factors for AKI identified may be modifiable.

Pulmonary artery hypertension in heart transplant recipients: how much is too much?

OBJECTIVES Unresponsive pulmonary hypertension (PH) may contraindicate heart transplant since it implies poor early outcomes. The present study reports the effectiveness of oral perioperative sildenafil in allowing heart transplant candidacy and surgery in a selected group of patients initially deemed ineligible because of PH. METHODS Between May 2005 and December 2009, 31 consecutive patients (5 females, 9 with a history of idiopatic cardiomyopathy and 16 with a history of coronary artery disease, 10 with previous sternotomies, 71.42 ± 27.69 ml/min/m(2) mean preoperative epidermal growth factor receptor) were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-week trial, RHC disclosed PH reversibility (mean pulmonary vascular resistance index: 9.57 ± 4.07 WU, mean transpulmonary gradient 14.47 ± 5.66 mmHg and mean systolic pulmonary artery pressure: 68.96 ± 15.15 mmHg), allowing listing despite a higher risk for early post-transplant RV failure. Transplant protocol included donor/recipient size matching ≥ 0.8 and inhaled nitric oxide in the early postoperative period followed by reinstitution of oral sildenafil. RESULTS All patients underwent heart transplantation. Mean overall graft ischaemic time was 179 ± 47 min; mean donor recipient weight ratio was 1.04 ± 0.17. Right ventricular failure developed in three patients (9.6%) and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary haemodynamic profile normalization within the third postoperative month allowing weaning from sildenafil in the 30 hospital survivors. One-year RHC confirmed PH reversal (n = 29 patients, all who survived up to 1 year). CONCLUSIONS This pilot prospective uncontrolled trial suggests that oral sildenafil is effective in allowing candidacy, safe transplantation and postoperative pulmonary profile normalization in potential recipients initially disqualified because of PH.

Italian multicentre study on type A acute aortic dissection: a 33-year follow-up

OBJECTIVES Despite substantial progress in surgical techniques and perioperative management, the treatment and long-term follow-up of type A acute aortic dissection (AAD) still remain a major challenge. The objective of this retrospective, multicentre study was to assess in a large series of patients the early and long-term results after surgery for type A AAD. METHODS We analysed the preoperative, intraoperative and postoperative conditions of 1.148 consecutive patients surgically treated in seven large referral centres from 1981 to 2013. We applied to each patient three different multi-parameter risk profiles (preadmission risk, admission risk and post-surgery risk) in order to compare risk factors and outcome. Long-term Kaplan-Meier survival was evaluated. RESULTS The median age was 64 years and the male population was predominant (66%). Identified diagnosis of collagen disease was present in 9%, and Marfan syndrome in 5%. Bicuspid aortic valve was present in 69 patients (6%). Previous cardiac surgery was identified in 10% of the patients. During surgery, the native aortic valve was preserved in 72% of the cases, including leaflet resuspension in 23% and David operation in 1.2%. Considering aortic valve replacement (AVR: 28%), bioprosthesis implantation was performed in 14.7% of the subjects. Neurological impairment at discharge was shown in 23% of the cases among which 21% of patients had new neurological impairment versus preoperative conditions. The overall 30-day mortality rate was 25.7%. All risk profiles remained independently associated with in-hospital mortality. During the available follow-up of hospital survivors (median: 70 months, interquartile range: 34-113, maximum: 396), cardiac-related death occurred in 7.9% of the subjects. The cumulative survival rate for cardiac death was 95.3% at 5 years, 92.8% at 10 years and 52.8% at 20 years. Severe aortic regurgitation (AR) (grade 3-4) at the time of surgery showed to be a significant risk factor for reintervention during the follow-up (P < 0.001). Among risk profiles, only the preadmission risk was independently associated with late mortality after multivariate analysis. Unexpectedly, there was no difference in freedom from cardiac death between patients with and without AVR. CONCLUSIONS Although surgery for type A has remained challenging over more than three decades, there is a positive trend in terms of hospital mortality and long-term follow-up. About 90% of patients were free from reoperation in the long term, although late AR remains a critical issue, suggesting that a thorough debate on surgical options, assessment and results of a conservative approach should be considered.