Cristiano Amarelli

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.

Role of Sildenafil in Acute Posttransplant Right Ventricular Dysfunction: Successful Experience in 13 Consecutive Patients

BACKGROUND Superimposed acute right ventricular dysfunction in the setting of preexisting pulmonary hypertension is a nearly fatal complication after heart transplantation. The optimal treatment modality remains a matter of debate. Recently, sildenafil citrate, a nonselective pulmonary vasodilator, has gained popularity in the treatment of pulmonary hypertension in transplant candidates. METHODS Herein we have presented a series of 13 patients in whom sildenafil was used to treat right ventricular dysfunction and pulmonary hypertension as detected by transesophageal echocardiography and Swan-Ganz right heart catheterization after heart transplant. Their characteristics were mean age 49+/-11.4 years; 38.4% with previous cardiac procedures, 30.8% status I, basal pulmonary vascular resistance index 10.4+/-4.6 WoodU, mean transpulmonary gradient 18.7+/-5.4 mmHg. In addition to conventional inodilator support, we administered 1 to 3 mg per kilogram of sildenafil. Complete hemodynamic measurements were obtained before and after the institution of the therapy and at 1-month follow-up. RESULTS Within the first 72 hours, acute right ventricular dysfunction resolved in all cases without untoward side effects or significant systemic impact. Sildenafil significantly decreased the transpulmonary gradient and pulmonary vascular resistance index relative to baseline values; 5.6+/-1.82 versus 10.4+/-4.6 WU, (P< .05), 13.5+/-3.4 mm Hg versus 18.7+/-5.4 mm Hg (P< .05), respectively. Improved indices of right ventricular function were observed on echocardiographic monitoring. After 1 month, sildenafil treatment was discontinued. CONCLUSION Management of acute right ventricular dysfunction in heart transplant recipients with pulmonary hypertension using sildenafil proved safe and effective.

Coronary artery bypass grafting in patients with severe left ventricular dysfunction: A prospective randomized study on the timing of perioperative intraaortic balloon pump support

In this prospective trial the results of preoperative and intraoperative IABP in coronary artery bypass graft (CABG) patients with low left ventricular ejection fraction (LVEF) were compared. Sixty CABG patients with preoperative LVEF ≤0.30 were enrolled: in group A patients (n=30) IABP was started within 2 hours preoperatively; in group B (n=30) it was instituted intraoperatively before weaning from cardiopulmonary bypass. Cardiac performance was assessed through Swan-Ganz catheter monitoring and daily echocardiography. Hospital survival, length of IABP support, intubation, ICU and hospital stay, need for postoperative inotropic drugs and incidence of myocardial infarction were compared between the two groups. Survival in group A patients proved significantly higher (P=0.047). Cardiac performance after myocardial revascularization improved in both groups with significantly better outcomes in group A patients (p<0.001). Doses of inotropic drugs (dobutamine, enoximone) were lower in group A (P=0.001; P=0.004) and duration shorter (p<0.001; p<0.001). No major IABP-related complication was observed.

Deep sternal wound infection: the role of early debridement surgery

OBJECTIVE This retrospective chart review study aimed to evaluate whether a more aggressive staged approach can reduce morbidity and mortality following post-cardiotomy deep sternal wound infection. METHODS Between 1979 and 2000, 14620 patients underwent open heart surgery: mediastinitis developed in 124 patients (0.85%). Patients were divided in two groups: in 62 patients (Group A) (1979-1994) an initial attempt of conservative antibiotic therapy was the rule followed by surgical approach in case of failure; in 62 patients (Group B) (1995-2000) the treatment was staged in three phases: (1) wound debridement, removal of wires and sutures, closed irrigation for 10 days; (2) in case of failure open dressing with sugar and hyperbaric therapy (11 patients, 17%); (3) delayed healing and negative wound cultures mandated plastic reconstruction (three patients, 4%). Categorical values were compared using the Chi-square test, continuous data were compared by unpaired t-test. RESULTS Incidence of mediastinitis was higher in Group B (62 out of 5535; 1.3%) than in Group A (62 out of 9085; 0.7%) (P=0.007). Mean interval between diagnosis and treatment was shorter in Group B (18+/-6 days) than in group A (38+/-7 days) (P=0.001). Hospital mortality was higher in Group A (19/62; 31%) than in Group B (1 out of 62; 1.6%) (P<0.001). Hospital stay was shorter in Group B (30.5+/-3 days) than in group A (44+/-9 days) (P=0.001). In Group B complete healing was observed in all the 61 survivors: 47 cases (76%) after Stage 1; 11 (18%) after Stage 2; three (4.8%) after Stage 3. CONCLUSIONS Although partially biased by the fact that the two compared groups draw back to different decades, this study showed that an aggressive therapeutic protocol can significantly reduce morbidity and mortality of deep sternal wound infection.

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.

Surgical repair of acute type A aortic dissection: continuous pulmonary perfusion during retrograde cerebral perfusion prevents lung injury in a pilot study.

OBJECTIVE Postoperative respiratory failure is a frequent and serious complication in patients with type A acute aortic dissection operated on with deep systemic hypothermia. Interaction between neutrophils and pulmonary endothelium along with ischemic insult and reperfusion are the major determinants of lung injury. The aim of this prospective study was to evaluate the effect of continuous pulmonary perfusion during retrograde cerebral perfusion on lung function. METHODS Twenty-two patients referred for acute type A aortic dissection, who were free from preoperative respiratory dysfunction, were assigned prospectively and alternately to one of 2 treatment groups. Pulmonary perfusion was performed during retrograde cerebral perfusion in group B (11 patients), whereas the conventional Ueda technique was applied in group A (11 patients). Lung function was evaluated on the basis of intubation time, scoring of chest radiographs at 12 hours after cardiopulmonary bypass, and Pao(2)/fraction of inspired oxygen ratio assessed from immediately before the operation to 72 hours after termination of cardiopulmonary bypass. RESULTS Study groups were homogeneous for age, sex, interval between symptom onset and surgical operation, previous aortic surgery, preoperative ejection fraction and pulmonary gas exchange function, extent of aortic repair, and concomitant procedures. Cardiopulmonary bypass time, length of retrograde cerebral perfusion, operation time, need for blood substitutes, and surgical revision for bleeding did not differ between treatment groups. Postoperative Pao(2)/fraction of inspired oxygen ratios were higher in group B than in group A, and the difference remained statistically significant throughout the study period. The incidence of prolonged ventilator support (>72 hours) and the severity of the radiographic pulmonary infiltrate score were lower in the perfused group (18.2% vs 72.7% [P =.015] and 0.81 +/- 0.75 vs 1.8 +/- 0.78 [P =.028], respectively). CONCLUSIONS Continuous pulmonary perfusion provided a better preservation of lung function in patients operated on with deep systemic hypothermia.

Cardiac primitive cells become committed to a cardiac fate in adult human heart with chronic ischemic disease but fail to acquire mature phenotype: genetic and phenotypic study

Adult human heart hosts a population of cardiac primitive CD117-positive cells (CPCs), which are responsible for physiological tissue homeostasis and regeneration. While the bona fide stem cells express telomerase, their progenies are no longer able to preserve telomeric DNA; hence the balance between their proliferation and differentiation has to be tightly controlled in order to prevent cellular senescence and apoptosis of CPCs before their maturation can be accomplished. We have examined at cellular and molecular level the proliferation, apoptosis and commitment of CPCs isolated from normal (CPC-N) and age-matched pathological adult human hearts (CPC-P) with ischemic heart disease. In the CPC-P, genes related to early stages of developmental processes, nervous system development and neurogenesis, skeletal development, bone and cartilage development were downregulated, while those involved in mesenchymal cell differentiation and heart development were upregulated, together with the transcriptional activation of TGFβ/BMP signaling pathway. In the pathological heart, asymmetric division was the prevalent type of cardiac stem cell division. The population of CPC-P consisted mainly of progenitors of cardiac cell lineages and less precursors; these cells proliferated more, but were also more susceptible to apoptosis with respect to CPC-N. These results indicate that CPCs fail to reach terminal differentiation and functional competence in pathological conditions. Adverse effects of underlying pathology, which disrupts cardiac tissue structure and composition, and cellular senescence, resulting from cardiac stem cell activation in telomere dysfunctional environment, can be responsible for such outcome.

Early graft failure after heart transplant: risk factors and implications for improved donor-recipient matching.

Early graft failure (EGF) is a dreaded complication after heart transplantation (HT). Despite several improvements, no effective therapy has been developed and the prognosis is poor. We evaluated the risk factors and clinical impact of EGF. In a consecutive series of 317 HTs performed at a single institution between January 1999 and December 2008, variables associated significantly with EGF were sought in bivariate and multivariable discriminant analyses. The deriving propensity score was used to stratify the study sample in to three groups (low, intermediate and high risk for EGF). Comparisons were performed between the higher-risk group and the remaining population in terms of preoperative features and outcomes. EGF occurred in 10.1% of the overall population (2.9, 3.8 and 23.6%, respectively, in the three groups). Overall, EGF-related mortality was 56.3% (100, 75 and 48%, respectively, in the three groups). Determinants of EGF in the highest-risk group were: redo procedure, valvular cardiomyopathy, status one at transplant, recipient male sex, donor-recipient (D/R) weight mismatch, high inotropic donor support, ischaemic time and first day troponin I release. In conclusion, several donor and recipient features predicted EGF. Since such characteristics are not readily modifiable but synergistically determine the occurrence of EGF, optimization of D/R matching is crucial to prevent it.

High-risk heart grafts: effective preservation with Celsior solution.

Celsior solution has already proved effective in heart graft preservation because it reduces myocardial edema, prevents free radical damage, and limits calcium overload. The aim of this study was to evaluate the effectiveness of Celsior solution as myocardial protection in high-risk transplantation. Hospital charts and follow-up data of 200 consecutive heart recipients (162 males, 38 females, mean age 47.4 ± 12.6 years) were reviewed. Patients were divided into two groups: group A (73 patients) included recipients of high-risk grafts (at least two of the following: age >45; female sex; high preretrieval inotropic support, viz. dobutamine or dopamine >10 µg/kg per minute and/or infusion of norepinephrine regardless of its dosage; size mismatch >20%; ischemia time >180 min) and group B (127 patients) included recipients of standard grafts. Quality of preservation was assessed through enzyme release, echocardiographic evaluation, the need for inotropic support or pacemaker, and histology of biopsy samples. Hospital and 1-year mortality were also evaluated. Comparisons between the two groups were made through univariate analysis. Study groups proved homogeneous as to recipient age, pretransplant cardiomyopathy, status at transplantation, mean panel reactive antibodies, and redo cardiac surgery. Hospital mortality was 8% (11% vs 6.3%, P = 0.18) while 1-year mortality reached 12% (15.1% vs 10.2%, P = 0.6) without significant difference between groups. Graft performance as described by the need for inotropic support and/or pacemaker as well as echocardiography (left and right ventricular ejection fraction) proved comparable. There were no significant differences as to histology findings and patterns of enzyme release. Celsior provides optimal myocardial preservation in both standard and high-risk procedures. Such advances help to enhance donor pool expansion.