Impairment of Angiogenesis-Driven Clot Resolution Is a Key Event in the Progression to Chronic Thromboembolic Pulmonary Hypertension: Validation in a Novel Rabbit Model.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition and rare complication of acute pulmonary embolism. Mechanisms underlying impaired clot resolution and in sustained fibrothrombotic obstruction of the pulmonary arterial bed remain poorly understood. Since defective angiogenesis correlated to defective clot resolution based on observations in surgical material from patients with CTEPH, we aimed to validate its crucial pathogenic role by intrathrombus inhibition of angiogenesis in a novel CTEPH rabbit model. METHODS: We aimed to compare whether intrathrombus administration of an antifibrinolytic agent, tranexamic acid, or an inhibitor of angiogenesis, SU5416, would contribute to CTEPH progression. Both products were administered on a weekly basis by autologous clot embolization in rabbits. Right ventricular pressure was monitored by telemetry, right ventricular function by transthoracic echocardiography, and a complete pulmonary hemodynamic evaluation was obtained through right heart catheterization. Markers of inflammation, endothelial dysfunction, heart failure, and fibrinolysis were measured in plasma. Pulmonary vessel remodeling was analyzed by immunohistochemistry. RESULTS: Impairing intrathrombus angiogenesis by repeatedly embolizing autologous blood clots containing SU5416 resulted in elevated mean pulmonary arterial pressure (38 mm Hg), increased indexed pulmonary vascular resistance, and enhanced right ventricular hypertrophy (80%, 1.9-fold, 36%, respectively, compared with rabbits embolized with clots containing an antifibrinolytic agent). This was caused by both obstruction of large pulmonary arteries with fibrothrombotic material and muscularization of pulmonary microvessels, and accompanied by inflammatory cell infiltration and increased circulating endothelin-1. CONCLUSIONS: The key role of angiogenesis-driven clot resolution was validated in a reliable small-animal model reproducing the major pathophysiological hallmarks of CTEPH.

Donor heart selection: Evidence-based guidelines for providers.

The proposed donor heart selection guidelines provide evidence-based and expert-consensus recommendations for the selection of donor hearts following brain death. These recommendations were compiled by an international panel of experts based on an extensive literature review.

The novel proteomic signature for cardiac allograft vasculopathy.

AIMS: Cardiac allograft vasculopathy (CAV) is the major long-term complication after heart transplantation, leading to mortality and re-transplantation. As available non-invasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV. METHODS AND RESULTS: We measured urinary proteome by capillary electrophoresis coupled with mass spectrometry in 217 heart transplantation recipients (mean age: 55.0 ± 14.4 years; women: 23.5%), including 76 (35.0%) patients with CAV diagnosed by coronary angiography. We randomly and evenly grouped participants into the derivation cohort (n = 108, mean age: 56.4 ± 13.8 years; women: 22.2%; CAV: n = 38) and the validation cohort (n = 109, mean age: 56.4 ± 13.8 years; women: 24.8%, CAV: n = 38), stratified by CAV. Using the decision tree-based machine learning methods (extreme gradient boost), we constructed a proteomic signature for CAV discrimination in the derivation cohort and verified its performance in the validation cohort. The proteomic signature that consisted of 27 peptides yielded areas under the curve of 0.83 [95% confidence interval (CI): 0.75-0.91, P < 0.001] and 0.71 (95% CI: 0.60-0.81, P = 0.001) for CAV discrimination in the derivation and validation cohort, respectively. With the optimized threshold of 0.484, the sensitivity, specificity, and accuracy for CAV differentiation in the validation cohort were 68.4%, 73.2%, and 71.6%, respectively. With adjustment of potential clinical confounders, the signature was significantly associated with CAV [adjusted odds ratio: 1.31 (95% CI: 1.07-1.64) for per 0.1% increment in the predicted probability, P = 0.012]. Diagnostic accuracy significantly improved by adding the signature to the logistic model that already included multiple clinical risk factors, suggested by the integrated discrimination improvement of 9.1% (95% CI: 2.5-15.3, P = 0.005) and net reclassification improvement of 83.3% (95% CI: 46.7-119.5, P < 0.001). Of the 27 peptides, the majority were the fragments of collagen I (44.4%), collagen III (18.5%), collagen II (3.7%), collagen XI (3.7%), mucin-1 (3.7%), xylosyltransferase 1 (3.7%), and protocadherin-12 (3.7%). Pathway analysis performed in Reactome Pathway Database revealed that the multiple pathways involved by the signature were related to the pathogenesis of CAV, such as collagen turnover, platelet aggregation and coagulation, cell adhesion, and motility. CONCLUSIONS: This pilot study identified and validated a urinary proteomic signature that provided a potential approach for the surveillance of CAV. These proteins might provide insights into CAV pathological processes and call for further investigation into personalized treatment targets.

Speckle-tracking-based global longitudinal and circumferential strain detect early signs of antibody-mediated rejection in heart transplant patients.

AIMS: Acute rejection is an important cause of mortality after heart transplant (HTx), but symptoms develop only when myocardial damage is already extensive. We sought to investigate if echocardiographic parameters can detect and predict an acute cellular rejection (ACR) or antibody-mediated rejection (AMR) episode in HTx patients. METHODS AND RESULTS: Data of 403 consecutive HTx recipients between 2003 and 2020 from our centre were reviewed. Patients with severe ACR (n = 10) and AMR (n = 7) were identified. Each HTx patient presenting with rejection was matched to a control HTx patient. Echocardiographic variables from the moment of rejection and 3, 6, and 12 months before were analysed and compared among groups. At acute rejection episode, patients with rejection had lower values of global longitudinal strain (GLS), global circumferential strain (GCS), and left ventricular ejection fraction (LVEF) compared to controls. HTx patients with AMR showed a progressive decline of GLS and GCS in the months preceding acute rejection, while controls and ACR patients had stable strain values except for the moment of rejection. In our cohort, a GLS cut-off lower than 15.5% and a GCS cut-off lower than 15.2% could distinguish with a sensitivity and specificity of 100.0% AMR from controls 3 months before rejection. LVEF and other conventional echo parameters could not differentiate among groups. CONCLUSION: GLS and GCS show a progressive decrease months before AMR becomes clinically apparent. Our data suggest that global strain assessment by echocardiography allows an early detection of a developing AMR, which could improve the clinical management of HTx patients.

Relationship of Mechanical Dyssynchrony and LV Remodeling With Improvement of Mitral Regurgitation After CRT.

OBJECTIVES: The aim of this study was to explore the association between mechanical dyssynchrony of the left ventricle before cardiac resynchronization therapy (CRT) and improvement of mitral regurgitation (MR) after CRT. BACKGROUND: MR is very frequent among patients with dilated cardiomyopathy and conduction delay. METHODS: Echocardiograms (pre-CRT and 12 ± 3.8 months thereafter) of 314 patients with dilated cardiomyopathy and any degree of MR, who underwent CRT device implantation according to guidelines, were analyzed. Left ventricular (LV) mechanical dyssynchrony was assessed by apical rocking (ApRock) and septal flash (SF), while MR severity was graded from I to IV on the basis of vena contracta width, regurgitation jet size, and proximal isovelocity surface area. RESULTS: At baseline, 30% of patients presented with severe MR (grade III or IV). In 62% of patients, MR decreased after CRT, and these patients more frequently had left bundle branch block, had more severe MR, had more dilated left ventricles, had lower ejection fractions, and more often had ApRock and SF. Reverse remodeling was more frequent among patients with MR reduction (ΔLV end-systolic volume -35.5% ± 27.2% vs -4.1% ± 33.2%; P < 0.001). In a multivariable logistic stepwise regression, only ApRock (odds ratio [OR]: 3.8; 95% CI: 1.7-8.5; P = 0.001), SF (OR: 3.6; 95% CI: 1.6-7.9; P = 0.002), and baseline MR (OR: 1.4; 95% CI: 1.0-1.9; P = 0.046) remained significantly associated with MR reduction. CONCLUSIONS: ApRock, SF, and severity of MR at baseline are strongly associated with MR reduction after CRT, while LV reverse remodeling is its underlying mechanism. Therefore, in patients with heart failure with LV dyssynchrony on optimal medical treatment, CRT should be the primary treatment attempt for relevant MR.

Right ventricular and cyclic guanosine monophosphate signalling abnormalities in stages B and C of heart failure with preserved ejection fraction.

AIMS: Identifying early right ventricular (RV) dysfunction and impaired vasodilator reserve is challenging in heart failure with preserved ejection fraction (HFpEF). We hypothesized that cardiac magnetic resonance (CMR)-based exercise imaging and serial cyclic guanosine monophosphate (cGMP) measurements can identify dynamic RV-arterial uncoupling and responsiveness to pulmonary vasodilators at early stages of the HFpEF syndrome. METHODS AND RESULTS: Patients with HFpEF (n = 16), impaired left ventricular relaxation due to concentric remodelling (LVCR, n = 7), and healthy controls (n = 8) underwent CMR at rest and during supine bicycle exercise with simultaneous measurements of central haemodynamics and circulating cGMP levels, before and after oral administration of 50 mg sildenafil. At rest, mean pulmonary artery pressures (mPAP) were higher in HFpEF, compared with LVCR and controls (27 ± 2, 18 ± 1, and 11 ± 1, respectively; P = 0.01), whereas biventricular volumes, heart rate, and stroke volume were similar. During exercise, LVCR and HFpEF had a greater increase in the ratio of mPAP over cardiac output than controls (5.50 ± 0.77 and 6.34 ± 0.86 vs. 2.24 ± 0.55 in controls, P = 0.005). The ratio of peak exercise to rest RV end-systolic pressure-volume, a surrogate of RV contractility, was significantly reduced in LVCR and HFpEF (2.32 ± 0.17 and 1.56 ± 0.08 vs. 3.49 ± 0.35 in controls, P < 0.001) and correlated with peak exercise VO2 (R2  = 0.648, P < 0.001). cGMP levels increased with exercise across the HFpEF spectrum (P < 0.05 vs. baseline), except when postcapillary pulmonary hypertension was present at rest (P = 0.73 vs. baseline). A single sildenafil administration failed to increase circulating cGMP levels and did not improve RV performance. CONCLUSION: Exercise CMR identifies impaired RV-arterial coupling at an early stage of HFpEF. Circulating cGMP levels phenocopy the haemodynamic spectrum in HFpEF but fail to increase after phosphodiesterase type 5 inhibition, endorsing the need for alternative interventions to increase cGMP signalling in HFpEF.

Diagnosis, treatment, and follow-up of heart failure patients by general practitioners: A Delphi consensus statement.

AIMS: Creation of an algorithm that includes the most important parameters (history, clinical parameters, and anamnesis) that can be linked to heart failure, helping general practitioners in recognizing heart failure in an early stage and in a better follow-up of the patients. METHODS AND RESULTS: The algorithm was created using a consensus-based Delphi panel technique with fifteen general practitioners and seven cardiologists from Belgium. The method comprises three iterations with general statements on diagnosis, referral and treatment, and follow-up. Consensus was obtained for the majority of statements related to diagnosis, referral, and follow-up, whereas a lack of consensus was seen for treatment statements. Based on the statements with good and perfect consensus, an algorithm for general practitioners was assembled, helping them in diagnoses and follow-up of heart failure patients. The diagnosis should be based on three essential pillars, i.e. medical history, anamnesis and clinical examination. In case of suspected heart failure, blood analysis, including the measurement of NT-proBNP levels, can already be performed by the general practitioner followed by referral to the cardiologist who is then responsible for proper diagnosis and initiation of treatment. Afterwards, a multidisciplinary health care process between the cardiologist and the general practitioner is crucial with an important role for the general practitioner who has a key role in the up-titration of heart failure medication, down-titration of the dose of diuretics and to assure drug compliance. CONCLUSIONS: Based on the consensus levels of statements in a Delphi panel setting, an algorithm is created to help general practitioners in the diagnosis and follow-up of heart failure patients.

The Impact of Beta Blockers on Survival in Heart Transplant Recipients: Insights from the Zabrze HTx Registry.

INTRODUCTION: The data assessing the impact of beta blocker (BB) medication on survival in patients after heart transplantation (HTx) are scarce and unequivocal; therefore, we investigated this population. METHODS: We retrospectively analyzed the HTx Zabrze Registry of 380 consecutive patients who survived the 30-day postoperative period. RESULTS: The percentage of patients from the entire cohort taking BBs was as follows: atenolol 24 (17%), bisoprolol 67 (49%), carvedilol 11 (8%), metoprolol 28 (20%), and nebivolol 8 (6%). The patients receiving BBs were older (56.94 ± 14.68 years vs. 52.70 ± 15.35 years, p=0.008) and experienced an onset of HTx earlier in years (11.65 ± 7.04 vs. 7.24 ± 5.78 p ≤ 0.001). They also had higher hematocrit (0.40 ± 0.05 vs. 0.39 ± 0.05, p=0.022) and red blood cells (4.63 (106/µl) ± 0.71 vs. 4.45 (106/µl) ± 0.68, p=0.015). Survival according to BB medication did not differ among the groups (p=0.655) (log-rank test). Univariate Cox proportional hazard regression analysis revealed that the following parameters were associated with unfavorable diagnosis: serum concentration of albumin (g/l) HR: 0.87, 95% CI (0.81-0.94), p=0.0004; fibrinogen (mg/dl) HR: 1.006, 95% CI (1.002-1.008), p=0.0017; and C-reactive protein (mg/l) HR: 1.014, 95% CI (1.004-1.023), p=0.0044. CONCLUSIONS: The use of BBs in our cohort of patients after HTx was not associated with survival benefits.

The association of mechanical dyssynchrony and resynchronization therapy with survival in heart failure with a wide QRS complex: a two-world study.

Setting up a randomized trial to assess the association of mechanical dyssynchrony (MD) and the success of cardiac resynchronization therapy (CRT) in heart failure with a wide QRS complex is ethically challenging. We therefore investigated this association in a retrospective cohort study observing different treatment strategies which were chosen based on the availability of health care resources. The survival of 500 patients from six Western European centers treated with CRT was compared to their 137 Eastern European counterparts not treated with CRT, with regard to the presence of MD. MD was visually assessed and was defined as the presence of apical rocking and/or septal flash. Patients were followed for a mean of 26 ± 8 months for the occurrence of death of any cause. As compared with medical therapy alone, CRT was associated with a more favorable survival (hazard ratio (HR), 0.53; 95% confidence interval (CI) 0.35-0.79; P = 0.002). Patients with MD treated by CRT had better survival than patients belonging to all other groups-they showed 72%, 66% and 56% reduction in all-cause mortality, respectively, compared to patients with MD not treated by CRT (HR 0.28; 95% CI 0.17-0.44), patients without MD treated by CRT (HR 0.34; 95% CI 0.22-0.52) and patients without MD not treated by CRT (HR 0.44; 95% CI 0.25-0.76). Patients with wide QRS complex who are treated with CRT have a significantly better survival when MD is present.

Right Heart Catheterization-Background, Physiological Basics, and Clinical Implications.

The idea of right heart catheterization (RHC) grew in the milieu of modern thinking about the cardiovascular system, influenced by the experiments of William Harvey, which were inspired by the treatises of Greek philosophers like Aristotle and Gallen, who made significant contributions to the subject. RHC was first discovered in the eighteenth century by William Hale and was subsequently systematically improved by outstanding experiments in the field of physiology, led by Cournand and Dickinson Richards, which finally resulted in the implementation of pulmonary artery catheters (PAC) into clinical practice by Jeremy Swan and William Ganz in the early 1970s. Despite its premature euphoric reception, some further analysis seemed not to share the early enthusiasm as far as the safety and effectiveness issues were concerned. Nonetheless, RHC kept its significant role in the diagnosis, prognostic evaluation, and decision-making of pulmonary hypertension and heart failure patients. Its role in the treatment of end-stage heart failure seems not to be fully understood, although it is promising. PAC-guided optimization of the treatment of patients with ventricular assist devices and its beneficial introduction into clinical practice remains a challenge for the near future.

Sex-specific difference in outcome after cardiac resynchronization therapy.

AIMS: Observation of better outcome in women after cardiac resynchronization therapy (CRT) has led to controversies about a potential sex-specific response. In this study, we investigated to which extent this sex-specific difference in CRT outcome could be explained by differences in baseline characteristics between both sexes. METHODS AND RESULTS: We retrospectively analysed data from a multicentre registry of 1058 patients who received CRT. Patients were examined by echocardiography before and 12 ± 6 months after implantation. Response was defined as ≥15% reduction of left ventricular end-systolic volume at follow-up. Patient's characteristics at baseline, including New York Heart Association class, ejection fraction, QRS width and morphology, ischaemic aetiology of cardiomyopathy (ICM), number of scarred segments, age at implantation, atrial fibrillation, and mechanical dyssynchrony (Dyss) were analysed. Patients were followed for a median duration of 59 months. Primary end point was all-cause mortality. Women (24% of the population) had less ICM (23% vs. 49%, P < 0.0001), less scarred segments (0.4 ± 1.3 vs. 1.0 ± 2.1, P < 0.0001), more left bundle branch block (LBBB; 87% vs. 80%, P = 0.01), and more Dyss at baseline (78% vs. 57%, P < 0.0001). Without matching baseline differences, women showed better survival (log rank P < 0.0001). After matching, survival was similar (log rank P = 0.58). In multivariable analysis, female sex was no independent predictor of neither volumetric response (P = 0.06) nor survival (P = 0.31). CONCLUSION: Our data suggest that the repeatedly observed better outcome in women after CRT is mainly due to the lower rate ICM and smaller scars. When comparing patients with similar baseline characteristics, the response of both sexes to CRT is similar.

Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy.

Aim: To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. Methods and results: Echocardiography was performed in 1060 patients before and 12 ± 6 months after cardiac resynchronization therapy (CRT) implantation. Mechanical dyssynchrony, defined as the presence of apical rocking or septal flash was visually assessed at the baseline examination. Response was defined as ≥15% reduction in left ventricular end-systolic volume at follow-up. Patients were followed for a median of 59 months (interquartile range 37-86 months) for the occurrence of death of any cause. Applying the latest European guidelines retrospectively, 63.4% of the patients had been implanted with a Class I recommendation, 18.2% with Class IIa, 9.4% with Class IIb, and in 9% no clear therapy recommendation was present. Response rates were 65% in Class I, 50% in IIa, 38% in IIb patients, and 40% in patients without a clear guideline-based recommendation. Assessment of mechanical dyssynchrony improved response rates to 77% in Class I, 75% in IIa, 62% in IIb, and 69% in patients without a guideline-based recommendation. Non-significant difference in survival among guideline recommendation classes was found (Log-rank P = 0.2). Presence of mechanical dyssynchrony predicted long-term outcome better than guideline Classes I, IIa, IIb (Log-rank P < 0.0001, 0.006, 0.004, respectively) and in patients with no guideline recommendation (P = 0.02). Comparable results were observed using the latest American Guidelines. Conclusion: Our data suggest that current guideline criteria for CRT candidate selection could be improved by incorporating assessment of mechanical asynchrony.

Urinary proteomic signatures associated with ß-blockade and heart rate in heart transplant recipients.

OBJECTIVES: Heart transplant (HTx) recipients have a high heart rate (HR), because of graft denervation and are frequently started on ß-blockade (BB). We assessed whether BB and HR post HTx are associated with a specific urinary proteomic signature. METHODS: In 336 HTx patients (mean age, 56.8 years; 22.3% women), we analyzed cross-sectional data obtained 7.3 years (median) after HTx. We recorded medication use, measured HR during right heart catheterization, and applied capillary electrophoresis coupled with mass spectrometry to determine the multidimensional urinary classifiers HF1 and HF2 (known to be associated with left ventricular dysfunction), ACSP75 (acute coronary syndrome) and CKD273 (renal dysfunction) and 48 sequenced urinary peptides revealing the parental proteins. RESULTS: In adjusted analyses, HF1, HF2 and CKD273 (p ≤ 0.024) were higher in BB users than non-users with a similar trend for ACSP75 (p = 0.06). Patients started on BB within 1 year after HTx and non-users had similar HF1 and HF2 levels (p ≥ 0.098), whereas starting BB later was associated with higher HF1 and HF2 compared with non-users (p ≤ 0.014). There were no differences in the urinary biomarkers (p ≥ 0.27) according to HR. BB use was associated with higher urinary levels of collagen II and III fragments and non-use with higher levels of collagen I fragments. CONCLUSIONS: BB use, but not HR, is associated with a urinary proteomic signature that is usually associated with worse outcome, because unhealthier conditions probably lead to initiation of BB. Starting BB early after HTx surgery might be beneficial.

Biomarkers to Assess Right Heart Pressures in Recipients of a Heart Transplant: A Proof-of-Concept Study.

BACKGROUND: This proof-of-concept study investigated the feasibility of using biomarkers to monitor right heart pressures (RHP) in heart transplanted (HTx) patients. METHODS: In 298 patients, we measured 7.6 years post-HTx mean pressures in the right atrium (mRAP) and pulmonary artery (mPAP) and capillaries (mPCWP) along with plasma high-sensitivity troponin T (hsTnT), a marker of cardiomyocyte injury, and the multidimensional urinary classifiers HF1 and HF2, mainly consisting of dysregulated collagen fragments. RESULTS: In multivariable models, mRAP and mPAP increased with hsTnT (per 1-SD, +0.91 and +1.26 mm Hg; P < 0.0001) and with HF2 (+0.42 and +0.62 mm Hg; P ≤ 0.035), but not with HF1. mPCWP increased with hsTnT (+1.16 mm Hg; P < 0.0001), but not with HF1 or HF2. The adjusted odds ratios for having elevated RHP (mRAP, mPAP or mPCWP ≥10, ≥24, ≥17 mm Hg, respectively) were 1.99 for hsTnT and 1.56 for HF2 (P ≤ 0.005). In detecting elevated RHPs, areas under the curve were similar for hsTnT and HF2 (0.63 vs 0.65; P = 0.66). Adding hsTnT continuous or per threshold or HF2 continuous to a basic model including all covariables did not increase diagnostic accuracy (P ≥ 0.11), whereas adding HF2 per optimized threshold increased both the integrated discrimination (+1.92%; P = 0.023) and net reclassification (+30.3%; P = 0.010) improvement. CONCLUSIONS: Correlating RHPs with noninvasive biomarkers in HTx patients is feasible. However, further refinement and validation of such biomarkers is required before their clinical application can be considered.

Reversibility of severe mitral valve regurgitation after left ventricular assist device implantation: single-centre observations from a real-life population of patients.

OBJECTIVES: This study evaluates the impact of untreated preoperative severe mitral valve regurgitation (MR) on outcomes after left ventricular assist device (LVAD) implantation. METHODS: Of the 234 patients who received LVAD therapy in our centre during a 6-year period, we selected those who had echocardiographic images of good quality and excluded those who underwent mitral valve replacement prior to or mitral valve repair during LVAD placement. The 128 patients selected were divided into 2 groups: Group A with severe MR (n = 65) and Group B with none to moderate MR (n = 63, 28 with moderate MR). We evaluated transthoracic echocardiography preoperatively [15 (7-28) days before LVAD implantation; median (interquartile range)] and postoperatively up to the last available follow-up [501 (283-848) days after LVAD]. We collected mortality, complications and clinical status indicators of the patient cohort. RESULTS: We observed a significant decrease in the severity of MR after LVAD implantation (severe MR 51% pre- vs 6% post-LVAD implantation, P < 0.001). There was no difference between groups in terms of right heart failure, rate of urgent heart transplantation, pump thrombosis or ventricular arrhythmias. There was no difference in 1-year survival and 3-year survival (87.7% vs 88.4% and 71.8% vs 66.6% for Groups A and B, respectively, P = 0.97). CONCLUSIONS: Preoperative severe MR resolves in the majority of patients early on after LVAD implantation and is not associated with worse clinical outcomes or intermediate-term survival.

The association of volumetric response and long-term survival after cardiac resynchronization therapy.

AIMS: Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may not necessarily imply non-response to cardiac resynchronization therapy (CRT). We investigated the association of the extent of LV remodelling, mechanical dyssynchrony, and survival in patients undergoing CRT. METHODS AND RESULTS: In 356 CRT candidates, three blinded readers visually assessed the presence of mechanical dyssynchrony (either apical rocking and/or septal flash) before device implantation and also its correction by CRT 12 ± 3 months post-implantation. To assess LV reverse remodelling, end-systolic volumes (ESV) were measured at the same time points. Patients were divided into four subgroups: no LV remodelling (ESV change 0 ± 5%), mild LV reverse remodelling (ESV reduction 5-15%), significant LV reverse remodelling (ESV reduction ≥15%), and LV volume expansion (ESV increase ≥5%). Patients were followed for all-cause mortality during the median follow-up of 36 months. Patients with LV remodelling as in the above defined groups showed 58, 54, and 84% reduction in all-cause mortality compared to patients with volume expansion. In multivariable analysis, LVESV change remained independently associated with survival, with an 8% reduction in mortality for every 10% decrease in LVESV (P = 0.0039), but an optimal cut-off point could not be established. In comparison, patients with corrected mechanical dyssynchrony showed 71% reduction in all-cause mortality (P < 0.001). CONCLUSION: Volumetric response assessed at 1-year after CRT is strongly associated with long-term mortality. However, an optimal cut-off cannot be established. The association of the correction of mechanical dyssynchrony with survival was stronger than that of any volumetric cut-off.

Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET)-Rationale and database description.

OBJECTIVES: Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET; NCT03152422) aims: (i) to construct new multidimensional urinary proteomic (UP) classifiers that after heart transplantation (HTx) help in detecting graft vasculopathy, monitoring immune system activity and graft performance, and in adjusting immunosuppression; (ii) to sequence UP peptide fragments and to identify key proteins mediating HTx-related complications; (iii) to validate UP classifiers by demonstrating analogy between UP profiles and tissue proteomic signatures (TP) in diseased explanted hearts, to be compared with normal donor hearts; (iv) and to identify new drug targets. This article describes the uPROPHET database construction, follow-up strategies and baseline characteristics of the HTx patients. METHODS: HTx patients enrolled at the University Hospital Gasthuisberg (Leuven) collected mid-morning urine samples. Cardiac biopsies were obtained at HTx. UP and TP methods and the statistical work flow in pursuit of the research objectives are described in detail in the Data supplement. RESULTS: Of 352 participants in the UP study (24.4% women), 38.9%, 40.3%, 5.7% and 15.1% had ischemic, dilated, hypertrophic or other cardiomyopathy. The median interval between HTx and first UP assessment (baseline) was 7.8 years. At baseline, mean values were 56.5 years for age, 25.2 kg/m2 for body mass index, 142.3/84.8 mm Hg and 124.2/79.8 mm Hg for office and 24-h ambulatory systolic/diastolic pressure, and 58.6 mL/min/1.73 m2 for the estimated glomerular filtration rate. Of all patients, 37.2% and 6.5% had a history of mild (grade = 1B) or severe (grade ≥ 2) cellular rejection. Anti-body mediated rejection had occurred in 6.2% patients. The number of follow-up urine samples available for future analyses totals over 950. The TP study currently includes biopsies from 7 healthy donors and 15, 14, and 3 patients with ischemic, dilated, and hypertrophic cardiomyopathy. CONCLUSIONS: uPROPHET constitutes a solid resources for UP and TP research in the field of HTx and has the ambition to lay the foundation for the clinical application of UP in risk stratification in HTx patients.