Cardiac Rehabilitation in Patients With Ventricular Assist Device.

PURPOSE: The aim of this study was to investigate changes in exercise capacity (EC) and quality of life (QoL) of patients with ventricular assist devices (VADs) during cardiac rehabilitation (CR). METHODS: Data from patients with VAD implantation and subsequent CR between 2007 and 2017 were analyzed retrospectively. Measures of the 6-min walk test [6MWT] distance, Functional Independence Measure [FIM], ergometry, MacNew Heart Disease Questionnaire [MNH], and Hospital Anxiety and Depression Scale [HADS] at entry and discharge were examined. RESULTS: Data from 110 patients (age 53 ± 12 yr; male 82%) were analyzed. Patients improved during CR significantly in the 6MWT (114 ± 85 m, P < .001), ergometry (20 ± 17 W, P = .002), FIM (8 ± 7 points, P < .001), and MNH (0.8 ± 0.7 points, P < .001). Initial HADS levels were high with a mean value of 9 and did not improve during CR (-0.4 ± 5 points, P = .637). Significant differences of improvements in the 6MWT were observed between left and biventricular VAD (129 ± 90 m vs 85 ± 67 m, P = .043) as well as destination therapy and bridge-to-transplant (184 ± 88 m vs 102 ± 82 m, P = .005). CONCLUSIONS: Patients with VAD implantation had statistically and clinically significant improvements in EC and QoL as assessed with the MNH during CR. Patients on destination therapy showed a larger benefit from CR than bridge-to-transplant patients and patients with left VAD improved more than biventricular VAD patients.

Implementation and management outcomes of pharmacogenetic CYP2C19 testing for clopidogrel therapy in clinical practice.

PURPOSE: The antiplatelet prodrug clopidogrel is bioactivated by the polymorphic enzyme CYP2C19. Prospective clinical studies demonstrated an association between CYP2C19 loss of function (LoF) variants and an increased risk of thrombotic events under clopidogrel, but pharmacogenetic (PGx) testing is not frequently implemented in clinical practice. We report our experience with PGx-guided clopidogrel therapy with particular regard to clinically relevant patient management changes. METHODS: We conducted an observational study analyzing patients that underwent PGx testing for clopidogrel therapy at two Swiss hospitals. Primary outcome was the proportion of patients with clinically relevant PGx-based management recommendations and their implementation. The association of recurrent ischemic events under clopidogrel with CYP2C19 LoF variants and other factors was explored in a multivariate case-control analysis. RESULTS: Among 56 patients undergoing PGx testing, 18 (32.1%) were classified as CYP2C19 intermediate or poor metabolizers. This resulted in 17 recommendations for a change of antiplatelet therapy, which were implemented in 12 patients (70.1%). In the remaining five patients, specific reasons for non-implementation could be identified. Recurrent ischemic events under clopidogrel were associated with LoF variants (OR 2.2, 95% CI 0.3-14.4) and several cardiovascular risk factors. Associations were not statistically significant in our small study, but plausible and in line with estimates from large prospective studies. CONCLUSION: PGx-guided clopidogrel therapy can identify patients with an elevated risk of ischemic events and offer evidence-based alternative treatments. Successful implementation in clinical practice requires a personalized interdisciplinary service that evaluates indications and additional risk factors, provides specific recommendations, and proactively follows their implementation.

Duration of Pre-Operative Antibiotic Treatment and Culture Results in Patients With Infective Endocarditis.

BACKGROUND: Bacterial growth in cultures of resected heart valves of patients with infective endocarditis (IE) is influenced by pre-operative antibiotic treatment (preop-AT). OBJECTIVES: This study sought to evaluate the time dependency of valve culture results (positive valve culture [PVC] vs. negative valve culture) on preop-AT. METHODS: A total of 352 IE episodes in 344 adult patients of our tertiary referral hospital were retrospectively investigated (2005 to 2016). The primary endpoint was PVC results. The study used a logistic additive model adjusted for bacterial species, the McCabe-Jackson classification, and the existence of foreign valve material as covariables. RESULTS: The 231 included IE cases (187 [81%] men, median age 62 years, 153 [66%] native valves) comprised 58 (25%) PVC results and 173 (75%) negative valve culture results. A multivariable analysis adjusted for bacterial species, McCabe-Jackson classification, and valve type resulted in odds ratios for PVC of 6.35 (95% confidence interval [CI]: 1.94 to 20.78; p = 0.002) and 3.93 (95% CI: 1.57 to 9.84; p = 0.003) for Enterococcus spp. and Staphylococcus spp., respectively. Model-based odds ratios for PVC risk reduction in 2-day intervals of preop-AT ranged from 0.64 (95% CI: 0.61 to 0.68) at day 7 to 0.74 (95% CI: 0.70 to 0.78) at day 13 and 0.98 (95% CI: 0.93 to 1.02) at day 21. CONCLUSIONS: In IE cases treated with valve surgery, Staphylococcus aureus and Enterococcus spp. were associated with valve culture growth. After 7 days of antibiotic treatment, the additional effect of preop-AT on valve culture results per 2-day interval was minor. Antibiotic treatment beyond 21 days had no influence on culture results.

Hypertonic saline for fluid resuscitation in ICU patients post-cardiac surgery (HERACLES): a double-blind randomized controlled clinical trial.

PURPOSE: Recent evidence questions a liberal approach to fluid resuscitation in intensive care unit (ICU) patients. Here, we assess whether use of hypertonic saline applied as single infusion at ICU admission after cardiac surgery can reduce cumulative perioperative fluid volume. METHODS: Prospective randomized double-blind single-center clinical trial investigates effects of a single infusion of hypertonic saline (HS) versus normal saline (comparator). Primary endpoint was the cumulative amount of fluid administered in patients in the hypertonic saline versus the 0.9% saline groups (during ICU stay). Upon ICU admission, patients received a single infusion of 5 ml/kg body weight of 7.3% NaCl (or 0.9% NaCl) over 60 min. Patients undergoing cardiac surgery for elective valvular and/or coronary heart disease were included. Patients with advanced organ dysfunction, infection, and/or patients on chronic steroid medication were excluded. RESULTS: A total of 101 patients were randomized to receive the study intervention (HS n = 53, NS n = 48). Cumulative fluid intake on the ICU (primary endpoint) did not differ between the HS and the NS groups [median 3193 ml (IQR 2052-4333 ml) vs. 3345 ml (IQR 2332-5043 ml)]. Postoperative urinary output until ICU discharge was increased in HS-treated patients [median 2250 ml (IQR 1640-2690 ml) vs. 1545 ml (IQR 1087-1976 ml)], and ICU fluid balance was lower in the HS group when compared to the NS group [296 ml (IQR - 441 to 1412 ml) vs. 1137 ml (IQR 322-2660 ml)]. CONCLUSION: In a monocentric prospective double-blind randomized clinical trial, we observed that hypertonic saline did not reduce the total fluid volume administered on the ICU in critically ill cardiac surgery patients. Hypertonic saline infusion was associated with timely increase in urinary output. Variations in electrolyte and acid-base homeostasis were transient, but substantial in all patients.

Cytokine Removal in Critically Ill Patients Requiring Surgical Therapy for Infective Endocarditis (RECReATE): An Investigator-initiated Prospective Randomized Controlled Clinical Trial Comparing Two Established Clinical Protocols.

INTRODUCTION: Infective endocarditis (IE) and other severe infections induce significant changes in the immune response in a considerable number of affected patients. Numerous IE patients develop a persistent functional immunological phenotype that can best be characterized by a profound anti-inflammation and/ or functional "anergy." This is pronounced in patients with unresolved infectious foci and was previously referred to as "injury-associated immunosuppression" (IAI). IAI can be assessed by measurement of the monocytic human leukocyte antigen-DR (mHLA-DR) expression, a global functional marker of immune competence. Persistence of IAI is associated with prolonged intensive care unit length of stay, increased secondary infection rates, and death. Immunomodulation to reverse IAI was shown beneficial in early immunostimulatory (randomized controlled) clinical trials. METHODS: Prospective 1:1 randomized controlled clinical study to compare the course of mHLA-DR in patients scheduled for cardiac surgery for IE. Patients will receive either best standard of care plus cytokine adsorption during surgery while on cardiopulmonary bypass (protocol A) versus best standard of care alone, that is, surgery without cytokine adsorption (protocol B). A total of 54 patients will be recruited and randomized. The primary endpoint is a change in quantitative expression of mHLA-DR (antibodies per cell on CD14+ monocytes/ macrophages, assessed using a quantitative standardized assay) from baseline (preoperation [pre-OP], visit 1) to day 1 post-OP (visit 4). DISCUSSION: This randomized controlled clinical trial (RECReATE) will compare 2 clinical treatment protocols and will investigate whether cytokine adsorption restores monocytic immune competence (reflected by increased mHLA-DR expression) in patients with IE undergoing cardiac surgery. TRIAL REGISTRATION: This protocol was registered in ClinicalTrials.gov, under number NCT03892174, first listed on March 27, 2019.

Rivaroxaban in patients with mechanical heart valves: A pilot study.

BACKGROUND: Patients with mechanical heart valves are still not eligible for treatment with direct oral anticoagulants (DOAC). We aimed to conduct a proof-of-principle study investigating the anti-Xa inhibitor rivaroxaban as antithrombotic treatment in patients with recent mechanical aortic valve replacement. MATERIALS AND METHODS: Low-risk patients scheduled for elective mechanical aortic valve replacement were treated with rivaroxaban 20 mg once daily (OD) in a prospective cohort study, started on day 3 postoperatively and given for 6 months. The study was registered at ClinicalTrials.gov (#NCT02128841). RESULTS: Ten patients were included (median age, 48; range 39 to 60). Indication was aortic valve stenosis in 6 patients, aortic root aneurysm with severe aortic valve regurgitation in 3 patients, and mixed stenosis/regurgitation in 1 patient. Neither thromboembolic nor bleeding events were observed, and no patient died. Absence of valve thrombosis was demonstrated in all patients. On day 7, median D-dimers were 2723 µg/L (inter-quartile range [IQR] 1672, 5695 µg/L), median TAT levels were 4.5 µg/L (IQR 4.1, 5.6 µg/L); and median peak thrombin generation was 150 nM (IQR 91, 183). On day 90, median D-dimers were 426 µg/L (IQR 278, 569), median TAT levels were 2.7 µg/L (IQR 2.2, 3.1), and median peak thrombin generation were 66 nM (IQR 62, 87). CONCLUSIONS: Rivaroxaban 20 mg OD was safe and effective in a pilot study of 10 low risk patients with mechanical aortic heart valve. Our results justify larger studies investigating the application of anti-Xa inhibitors in patients with mechanical heart valves.

Single-center experience with the combination of Cardioplexol™ cardioplegia and MiECC for isolated coronary artery bypass graft procedures.

BACKGROUND: Cardioplexol™ with its low volume (100 mL) was originally conceived as cardioplegic solution for MiECC procedures. Introduced in its current form in 2008 in our clinic, it has immediately demonstrated attractive advantages including the easy and rapid administration by the surgeon him/herself, the almost immediate cardiac arrest and a prolonged delay before a second dose is necessary. We report here the results of our initial experience with this simple solution. METHODS: Single centre, retrospective observational analysis of prospectively collected data of isolated coronary artery bypass graft (CABG) procedures performed with a MiECC. RESULTS: Of 7,447 adult cardiac surgical operations performed during a 76 months period, 2,416 were isolated CABG-MiECC procedures. Patients were 81.3% males, 66.2±9.7 years old and had a median logistic EuroSCORE of 3.2. In average 3.2±0.8 vessels were bypassed. Median cross-clamp time was 45 minutes and more than 75% of the patients received only one 100 mL dose of Cardioplexol™. At reperfusion more than 90% of the hearts spontaneously recovered a rhythmic activity. Maximal value of troponin T during the first hours following myocardial reperfusion was 0.9±4.5 ng/mL (median =0.4 ng/mL). Mortality at 30 days was 0.9%. CONCLUSIONS: Cardioplexol™ seems very promising. It appears especially efficient and safe when used for CABG procedures performed with a MiECC.

Hypertonic saline for fluid resuscitation after cardiac surgery (HERACLES): study protocol for a preliminary randomised controlled clinical trial.

BACKGROUND: Intraoperative and postoperative management of cardiac surgery patients is complex, involving the application of differential vasopressors and volume therapy. It has been shown that a positive fluid balance has a major impact on postoperative outcome. Today, the advantages and disadvantages of buffered crystalloid solutes are a topic of controversy, with no consensus being reached so far. The use of hypertonic saline (HS) has shown promising results with respect to lower total fluid balance and postoperative weight gain in critically ill patients in preliminary studies. However, collection of more data on HS in critically ill patients seems warranted. This preliminary study aims to investigate whether fluid resuscitation using HS in patients following cardiac surgery results in less total fluid volume being administered. METHODS: In a prospective double-blind randomised controlled clinical trial, we aim to recruit 96 patients undergoing elective cardiac surgery for ischaemic and/or valvular heart disease. After postoperative admission to the intensive care unit (ICU), patients will be randomly assigned to receive 5 ml/kg ideal body weight HS (7.3% NaCl) or normal saline (NS, 0.9% NaCl) infused within 60 min. Blood and urine samples will be collected preoperatively and postoperatively up to day 6 to assess changes in renal, cardiac, inflammatory, acid-base, and electrolyte parameters. Additionally, we will perform renal ultrasonography studies to assess renal blood flow before, during, and after infusion, and we will measure total body water using preoperative and postoperative body composition analysis (bioimpedance). Patients will be followed up for 90 days. DISCUSSION: The key objective of this study is to assess the cumulative amount of fluid administered in the intervention (HS) group versus control (NS) group during the ICU stay. In this preliminary, prospective, randomised controlled clinical trial we will test the hypothesis that use of HS results in less total fluids infused and less postoperative weight gain when compared to the standard of intensive care in cardiac surgery patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03280745 . Registered on 12 September 2017.

Fluid management in patients undergoing cardiac surgery: effects of an acetate- versus lactate-buffered balanced infusion solution on hemodynamic stability (HEMACETAT).

BACKGROUND: Recent evidence suggests that acetate-buffered infusions result in better hemodynamic stabilization than 0.9% saline in patients undergoing major surgery. The choice of buffer in balanced crystalloid solutions may modify their hemodynamic effects. We therefore compared the inopressor requirements of Ringer's acetate and lactate for perioperative fluid management in patients undergoing cardiac surgery. METHODS: Using a randomized controlled double-blind design, we compared Ringer's acetate (RA) to Ringer's lactate (RL) with respect to the average rate of inopressor administered until postoperative hemodynamic stabilization was achieved. Secondary outcomes were the cumulative dose of inopressors, the duration of inopressor administration, the total fluid volume administered, and the changes in acid-base homeostasis. Patients undergoing elective valvular cardiac surgery were included. Patients with severe cardiac, renal, or liver disease were excluded from the study. RESULTS: Seventy-five patients were randomly allocated to the RA arm, 73 to the RL. The hemodynamic profiles were comparable between the groups. The groups did not differ with respect to the average rate of inopressors (RA 2.1 mcg/kg/h, IQR 0.5-8.1 vs. RL 1.7 mcg/kg/h, IQR 0.7-8.2, p = 0.989). Cumulative doses of inopressors and time on individual and combined inopressors did not differ between the groups. No differences were found in acid-base parameters and their evolution over time. CONCLUSION: In this study, hemodynamic profiles of patients receiving Ringer's lactate and Ringer's acetate were comparable, and the evolution of acid-base parameters was similar. These study findings should be evaluated in larger, multi-center studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT02895659 . Registered 16 September 2016.

Clinical outcomes in high-risk patients with a severe aortic stenosis: a seven-year follow-up analysis.

INTRODUCTION: The aim of this study was to assess the clinical outcomes of high-risk patients with severe aortic stenosis (AS) allocated to medical treatment (MT), transcatheter aortic valve replacement (TAVR), and surgical aortic valve replacement (SAVR) through extended follow-up. METHODS AND RESULTS: Consecutive patients with severe symptomatic AS included in a prospective single centre registry underwent sweep follow-up between March and August 2016. Clinical outcomes were assessed using a competing risk model. A total of 442 patients (median age 83 years; 52% female) were allocated to MT (n = 78), SAVR (n = 107), or TAVR (n = 257) with a gradient of surgical risk as assessed by logistic EuroSCORE (MT: 27.9 ± 14.5%, TAVR: 24.7 ± 24.9%, SAVR: 12.5 ± 8.2%; p <0.001). Survival after a median duration of follow-up of seven years was 6.4% (MT), 30.4% (TAVR), and 46.7% (SAVR), respectively (p <0.001). One TAVR and one SAVR patient underwent repeat intervention for valvular degeneration between 4.5 and 8.4 years after intervention. Compromised left ventricular function (LVEF <40%) was associated with increased mortality (HR 1.62, 95% CI 1.22–2.15; p <0.0001), whereas female sex was protective (HR 0.68, 95% CI 0.53–0.88; p = 0.0006). CONCLUSION: Both TAVR and SAVR reduced mortality compared to MT throughout a median duration of follow-up of seven years. Repeat interventions for valvular degeneration were rare.

Mechanical complications in patients with ST-segment elevation myocardial infarction: A single centre experience.

BACKGROUND: The study aims to assess characteristics and outcomes of patients suffering a mechanical complication (MC) after ST-segment elevation myocardial infarction (STEMI) in a contemporary cohort of patients in the percutaneous coronary intervention era. METHODS AND RESULTS: This retrospective single-center cohort study encompasses 2508 patients admitted with STEMI between March 9, 2009 and June 30, 2014. A total of 26 patients (1.1%) suffered a mechanical complication: ventricular septal rupture (VSR) in 17, ventricular free wall rupture (VFWR) in 2, a combination of VSD and VFWR in 2, and papillary muscle rupture (PMR) in 5 patients. Older age (74.5 ± 10.4 years versus 63.9 ± 13.1 years, p < 0.001), female sex (42.3% versus 23.3%, p = 0.034), and a longer latency period between symptom onset and angiography (> 24h: 42.3% versus 16.2%, p = 0.002) were more frequent among patients with MC as compared to patients without MC. The majority of MC patients had multivessel disease (77%) and presented in cardiogenic shock (Killip class IV: 73.1%). Nine patients (7 VSR, 2 VFWR & VSR) were treated conservatively and died. Out of the remaining 10 VSR patients, four underwent surgery, three underwent implantation of an occluder device, and another three patients had surgical repair following occluder device implantation. All patients with isolated VFWR and PMR underwent emergency surgery. At 30 days, mortality for VSR, VFWR, VFWR & VSR and PMR amounted to 71%, 50%, 100% and 0%, respectively. CONCLUSIONS: Despite advances in the management of STEMI patients, mortality of mechanical complications stays considerable in this contemporary cohort. Older age, female sex, and a prolonged latency period between symptom onset and angiography are associated with the occurrence of these complications.

How to treat aortic graft infection? With a special emphasis on xeno-pericardial aortic tube grafts.

Infection of a vascular prosthesis or endovascular stent-graft is probably the most serious complication that may occur after implantation and dramatically affects the patient's outcome. The most common etiology of graft and/or prosthetic valve infection is usually wound-related infection, followed by seeding from distant infection sites (lung, urinary tract). Surgical treatment is almost always required but even after surgery, morbidity can be significant. Operative procedure must be tailored according to the individual patient and to the experience of the surgical team. Complete resection of the infected foreign material with débridement of the surrounding tissue gives most probably the best results. Orthotopic reconstruction is the best option for all thoracic and thoraco-abdominal pathologies and the use of coated prostheses, industrially fabricated bio-conduits, homografts or self-made vascular tubes from xenopericardial tissue has to be discussed from case to case. In some exceptional situations, endovascular stent-graft can be performed as bridging to a more complete treatment if general condition of the patient has to be stabilized.

Adding vancomycin to perioperative prophylaxis decreases deep sternal wound infections in high-risk cardiac surgery patients.

OBJECTIVES: Perioperative prophylaxis with cephalosporins reduces sternal wound infections (SWIs) after cardiac surgery. However, more than 50% of coagulase-negative staphylococci, an important pathogen, are cephalosporin resistant. The aim of this study was to determine the impact of adjunctive vancomycin on SWIs in high-risk patients. METHODS: We conducted a pre- and postintervention study in an academic hospital. Preintervention (2010-2011), all patients received prophylaxis with 1.5 g of cefuroxime for 48 h. During the intervention period (2012-2013), high-risk patients additionally received 1 g of vancomycin. High-risk status was defined as body mass index ≤18 or ≥ 30 kg/m2, reoperation, renal failure, diabetes mellitus, chronic obstructive pulmonary disease or immunosuppressive medication. Time series analysis was performed to study SWI trends and logistic regression to determine the effect of adding vancomycin adjusting for high-risk status. RESULTS: A total of 3902 consecutive patients (n = 1915 preintervention and n = 1987 postintervention) were included, of which 1493 (38%) patients were high-risk patients. In the high-risk group, 61 of 711 (8.6%) patients had SWI before and 30 of 782 (3.8%) patients after the intervention. Focusing on deep SWI (DSWI), 33 of 711 (4.6%) patients had DSWI before and 13 of 782 (1.7%) patients afterwards; the absolute risk difference of 2.9% yielded a number-needed-to-treat of 34 to prevent 1 DSWI. Corrected for high-risk status, adding vancomycin significantly reduced the overall SWI rate (odds ratio 0.42, 95% confidence interval 0.26-0.67; P < 0.001) and the subset of DSWI (odds ratio 0.30, 95% confidence interval 0.14-0.62; P = 0.001). The rate of SWI in low-risk patients remained unchanged. CONCLUSIONS: Adding vancomycin to standard antibiotic prophylaxis in high-risk patients significantly reduced DSWI after cardiac surgery.

Impact of new technologies and experience on procedural aspects of surgical aortic valve replacement - a process analysis.

BACKGROUND: Surgical aortic valve replacement (SAVR) is the treatment of choice in severe symptomatic aortic valve disease. New techniques and prostheses have been recently developed to facilitate the procedure and reduce aortic cross-clamp time (AOx). The aim of this study was to analyse the different procedural steps in order to identify the most time-consuming part during aortic clamping time and to compare impact of experience on procedural aspects. METHODS: AOx during SAVR was divided into five consecutive steps. Duration of each step was measured. The first procedural step started with clamping of the aorta and ended with the beginning of the second step starting with the resection of the native aortic valve. The third step started with placement of the first valve anchoring suture, the fourth step started with tying of the first suture and the fifth and final step started after the cut of the last suture and ended with removal of the aortic clamp. Surgeons were divided into two groups based on their experience, which in our analysis was defined as a total SAVR experience of more than 100 procedures. RESULTS: From March 2013 to August 2015 57 nonconsecutive patients (33% female; age, median 71.0 years, interquartile range 65.0-76.0) undergoing isolated SAVR for severe aortic valve stenosis in our institution were included in this process analysis. Two different prostheses were implanted. Forty-eight (84%) patients received a tissue valve (Perimount Magna Ease, Edwards Lifesciences, Irvine, USA) and 9 (16%) patients received a mechanical prosthesis (Medtronic AP 360, St-Paul, MN, USA). The mean estimated risk of mortality was 1.1% (0.7-1.6) according to the logistic EUROScore II. Overall duration of AOx was 50.5 ± 13.8 min, with 32.3% (16.4 ± 5.9 min) accounting for placing the sutures into the native annulus and the prosthetic sewing ring and 18.5% (9.2 ± 3.0min) accounting for tying and cutting the sutures. Surgeons with more experience performed 35 operations (61.4%) and needed an average of 44.1 ± 11.5 min versus 60.6 ± 11.0 min (p <0.001) for less experienced surgeons. Surgeons with more experience needed 14.0 ± 5.0 min for the suturing step and 8.4 ± 2.8 min for tying the sutures compared with 20.2 ± 5.2 min and 10.5 ± 3.0 min, respectively, for the less experienced surgeons with (p <0.001 and p = 0.010). CONCLUSION: Placing and tying sutures in the prostheses accounts for over half (50.8%) of AOx during isolated SAVR. Experienced surgeons have significantly reduced AOx. This shortening is equally distributed between all five procedural steps.

Steroids and Cardiopulmonary Bypass: a Never-ending Story.

This trial showed marginal beneficial effects of steroids on the coagulation system and clinical advantages in terms of bleeding and blood transfusion were minimal. This means that additional strategies to minimize blood transfusion are still required.

A simple preoperative score including the surgeon's experience to predict the probability of a successful mitral valve repair.

OBJECTIVES: According to recent guidelines, mitral valve (MV) repair is preferable to replacement. However, replacement is sometimes inevitable. Aims of the study were to identify variables that predict the risk of an unsuccessful MV repair and to evaluate a score that could help in planning MV surgical procedures. METHODS: Clinical data of all consecutive adult mitral valve surgical procedures, performed during a 50-month period, were extracted from our clinical registry, and combined with echocardiographic variables. The variables identified by a univariable analysis, together with factors known from the literature as indicating a possible risk of an unsuccessful MV repair, were compiled in a multivariable logistic regression analysis. The surgeon's experience was also taken into account. RESULTS: Of 545 MV procedures, 162 (29.7%) were MV replacements. Seven variables were identified as independent predictors of MV replacement (odd ratio; 95% CI): endocarditis (7.8; 3.7-16.5), absence of annular dilatation (3.6; 2.2-5.9), leaflet calcification (6.1; 3.0-12.7), annular calcification (3.7; 1.9-7.3), mitral stenosis (29.6; 9.3-93.8), mitral sclerosis (3.0; 1.7-5.3), surgeon's limited experience (3.9; 1.4-11.0). The ability of this model to discriminate between repair and replacement was calculated, and an area under the ROC curve of 0.87 was shown. A score was calculated for each patient and distributed into four risk categories: low risk (0-6), moderate risk (7-10), high risk (11-16) and very high risk (>16) of MV replacement with, respectively, 10.2 vs 10.0%, 40.5% vs 38.9%, 66.7 vs 70.4% and 93.2 vs 93.2% observed vs predicted probability of MV replacement. CONCLUSIONS: Preoperative assessment of seven variables can accurately predict the risk of an unsuccessful MV repair.

Targeted and global pharmacometabolomics in everolimus-based immunosuppression: association of co-medication and lysophosphatidylcholines with dose requirement.

INTRODUCTION: The immunosuppressive therapy with everolimus (ERL) after heart transplantation is characterized by a narrow therapeutic window and a substantial variability in dose requirement. Factors explaining this variability are largely unknown. OBJECTIVES: Our aim was to evaluate factors affecting ERL metabolism and to identify novel metabolites associated with the individual ERL dose requirement to elucidate mechanisms underlying ERL dose response variability. METHOD: We used liquid chromatography coupled with mass spectrometry for quantification of ERL metabolites in 41 heart transplant patients and evaluated the effect of clinical and genetic factors on ERL pharmacokinetics. Non-targeted plasma metabolic profiling by ultra-performance liquid chromatography and high resolution quadrupole-time-of-flight mass spectrometry was used to identify novel metabolites associated with ERL dose requirement. RESULTS: The determination of ERL metabolites revealed differences in metabolite patterns that were independent from clinical or genetic factors. Whereas higher ERL dose requirement was associated with co-administration of sodium-mycophenolic acid and the CYP3A5 expressor genotype, lower dose was required for patients receiving vitamin K antagonists. Global metabolic profiling revealed several novel metabolites associated with ERL dose requirement. One of them was identified as lysophosphatidylcholine (lysoPC) (16:0/0:0). Subsequent targeted analysis revealed that high levels of several lysoPCs were significantly associated with higher ERL dose requirement. CONCLUSION: For the first time, this study describes distinct ERL metabolite patterns in heart transplant patients and detected potentially new drug-drug interactions. The global metabolic profiling facilitated the discovery of novel metabolites associated with ERL dose requirement that might represent new clinically valuable biomarkers to guide ERL therapy.