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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. © 2022 International Society for Heart and Lung Transplantation

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.

Background Although arterial stiffness is an independent predictor of cardiovascular outcomes, its physiopathology remains unclear. Purpose This study aimed to investigate the urinary proteomic profile of aortic stiffness and provide insights into pathogenetic processes of arterial stiffness by pathway analysis. Methods In 669 participants (mean age, 50.5 years; 48.9% men) randomly recruited from the Flemish population, we measured carotid-femoral pulse wave velocity (PWV) by applanation tonometry. The proteomics of urine samples was quantified by using capillary electrophoresis coupled mass spectrometry. The proteomic data were analysed by the orthogonal projections to latent structures, a supervised dimensional reduction statistic method and summarised as a urinary proteomic (UP) score. Results The mean values were 7.56±2.02 m/s for PWV and 7.59±1.95 unit for the UP score. PWV was significantly associated with the UP score before and after adjustment for the potential covariates (β coefficient: 0.81 and 0.75, respectively; p Conclusions In conclusion, the urinary proteomic profile could be a new biomarker of aortic stiffness and the altered proteins may link to the underlying mechanisms and holds the potential to discover novel therapeutic targets for arterial stiffness. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The Internal Funds KU Leuven (STG-18-00379) Distribution and CorrelationThe Enrichment Pathways

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.

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

Introduction End-stage heart failure (HF) can be successfully treated with heart transplantation (HTx), which reduces mortality and improves quality of life (QoL). Diastolic dysfunction and subsequently increased left ventricular (LV) filling pressures can be an early sign of rejection, while later after HTx, they can be suggestive for other insults to the myocardium, for example related to transplant vasculopathy. Therefore, right heart catheterization (RHC) remains a standard follow-up examination in patients after HTx. It has been questioned, whether echocardiography can accurately predict the LV filling pressures in HTx patients, and whether echocardiographic diastolic parameters correlate with hemodynamics in this population. Therefore, our study aimed to investigate the correlation between invasive measurements and echocardiographic estimates of LV filling pressures in HTx patients. Methods We analyzed 461 consecutive HTx patients who underwent RHC and transthoracic echocardiography on the same day. Patients were classified as having elevated LV filling pressures when the pulmonary capillary wedge (PCWP) was ≥15 mmHg. Standard echocardiographic parameters of systolic and diastolic function were measured and the decision tree of the recommendations on diastolic dysfunction assessment of the American and European imaging societies (ASE/EACVI) was applied to detect elevated LV filling pressures and determine the diastolic dysfunction grade. Results The invasive measurements showed elevated LV filling pressures in 303 (66%) of HTx patients. Based on the echocardiographic parameters, HTx patients were classified into the following groups: normal diastolic function (n=151, 33%), grade I (n=87, 19%), grade II (n=21,5%), and grade III (n=151, 33%) diastolic dysfunction, and indetermined group (n=51, 11%). The PCWP values differed between the groups: 14.4±0.3 mmHg vs. 13.3±0.4 vs. 20.5±0.9 mmHg vs. 22.2±0.3 mmHg vs. 17.7±0.6 mmHg, p=0.0001, accordingly (Figure A). The PCWP showed moderate correlation with E/A (r=0.49, p=0.0001) and E/e' (r=0.40, p=0.0001) (Figures B and C, resp.). The decision tree of the ASE/EACVI recommendations predicted elevated LV filling pressures with a sensitivity of 64%, specificity of 98%, negative predictive value of 59% and positive predictive value (PPV) of 98%. Conclusions Our study is the first to demonstrate a correlation between the LV filling pressures estimated from echocardiography and invasively measured during RHC in large HTx population. Echocardiography alone can reliably describe elevated LV filling pressures with a high PPV. The sensitivity of the algorithm, however, is limited. Additional parameters need to be identified to increase the sensitivity of the current recommendations for detection of elevated filling pressures this patients population. Figure 1 Funding Acknowledgement Type of funding source: None

Purpose Cardiac transplantation from donation after circulatory death (DCD) has been implemented at our hospital since February 2015. Despite encouraging results some concerns may be raised about the impact of the warm ischemia and reperfusion injury on the myocardium status at longer follow-up. Therefore, we aimed to analyse systolic performance of the left ventricle at 1 year follow in DCD and donation after brain death (DBD) cardiac recipients, as assessed by echocardiography with myocardial deformation imaging. Methods We identified 46 consecutive DCD cardiac recipients who were transplanted from February 2015 to August 2018 and we matched them with 46 DBD cardiac recipients. Six and 7 patients from DCD and DBD group, respectively, died in the first-year post transplant. In the remaining patients we have compared the classical echocardiographic measurements as well as global longitudinal strain (GLS) and global circumferential strain (GCS) at 1-year follow-up. Results DCD and DBD patients did not present with differences in terms of classical echocardiographic parameters of left ventricular (LV) structure and systolic function at one-year follow-up. LVEDV was similar in DCD and DBD patients (101±24 vs. 95±32 ml, p=0.4 respectively), as well as LVESV (42±13 vs. 42±16 ml, p=0.9, respectively), LV ejection fraction (58±6 vs. 56±8%, p=0.22) and LV mass (156±39 vs. 163±38 gr, p=0.2, respectively). In contrast, myocardial deformation parameters, such as GLS and GCS, were better in DCD than in DBD (16.1 vs. −14.5%, p Conclusion DCD and DBD heart recipients present with similar systolic LV function at 1-year follow, as assessed by classical echocardiographic parameters. DCD cardiac recipients have better myocardial deformation parameters as assessed by the speckle tracking, better systolic right ventricular function and lower filling pressures of the left ventricle. Funding Acknowledgement Type of funding source: None

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 echocardio-graphic 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.

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.

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.MR is very frequent among patients with dilated cardiomyopathy and conduction delay.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.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.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.

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 +/- 6months 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 59months. 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.

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

Purpose Cardiac transplantation from donation after circulatory death (DCD) has been implemented at Papworth hospital since February 2015. Despite encouraging results some concerns may be raised about the impact of the warm ischemia and reperfusion injury on the myocardium status at longer follow-up. Therefore, we aimed to analyse systolic performance of the left ventricle at 1 year follow in DCD and donation after brain death (DBD) cardiac recipients, as assessed by echocardiography with myocardial deformation imaging. Methods We identified 26 DCD cardiac recipients who were transplanted from February 2015 to February 2017 and we matched them with 26 DBD cardiac recipients. Three and 2 patients from DCD and DBD group, respectively, died in the first-year post transplant. In the remaining patients we have compared the classical echocardiographic measurements as well as global longitudinal strain (GLS) and global circumferential strain (GCS) at 1-year follow-up. Results DCD and DBD patients did not present with differences in terms of classical echocardiographic parameters of left ventricular (LV) structure and systolic function. LVEDV was similar in DCD and DBD patients (102+/-37 vs. 99+/-21 ml, respectively), as well as LVESV (44+/-12 vs. 43 +/- 18 ml, respectively) and LV mass (157+/-36 vs. 169+/-44 gr). LV ejection fraction was similar in two groups (57+/- 7 vs. 58+/-8 %), as well as GLS (-15.9+/-2.3 vs. 14.8+/- 1.9%, p=0.1) and GCS (-23.7+/-5.7 vs. -20.3+/-4.1, p=0.05). In both groups 3 patients presented with left ventricular dysfunction secondary either to primary graft dysfunction or cellular rejection. When we limited analysis to the patients who presented at 1 year follow up with LVEF>=50%, DCD and DBD cardiac recipients presented with similar LVEF (60+/-5 vs. 58+/-4%), but DCD cardiac recipients in comparison to DBD recipients had better GLS (-16.5+/-1.7% vs. -15.1+/-1.4%, p=0.04) and better GCS (-25.2+/-4% vs. 20.9+/-3.25, p=0.02). Conclusion DCD and DBD cardiac recipients present with similar systolic LV function at 1-year follow, as assessed by classical echocardiographic parameters. DCD cardiac recipients have better myocardial deformation parameters as assessed by the speckle tracking in comparison to DBD cardiac recipients.

Aims Apical rocking (ApRock) and septal flash (SF) are often observed phenomena in asynchronously contracting ventricles. We investigated the relationship of visually assessed ApRock and SF, reverse remodelling, and long-term survival in cardiac resynchronization therapy (CRT) candidates. Methods and results A total of 1060 patients eligible for CRT underwent echocardiographic examinations before and 12 ± 6 months after device implantation. Three blinded physicians were asked to visually assess the presence of ApRock and SF before device implantation and also their correction by CRT 12 ± 6 months post-implantation. Patients with a left ventricular (LV) end-systolic volume decrease of ≥15% during the first year of follow-up were regarded as responders. Patients were followed for a median period of 46 months (interquartile range: 27–65 months) for the occurrence of death of any cause. If corrected by CRT, visually assessed ApRock and SF were associated with reverse remodelling with a sensitivity of 84 and 79%, specificity of 79 and 74%, and accuracy of 82 and 77%, respectively. ApRock (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.30–0.53, P < 0.0001) and SF (HR 0.45 [CI 0.34–0.61], P < 0.001) were independently associated with lower all-cause mortality after CRT and had an incremental value over clinical variables and QRS width for identifying CRT responders. Both the absence of ApRock/SF and unsuccessful correction of ApRock/SF despite CRT were associated with a high risk for non-response and an unfavourable long-term survival. Conclusion A specific LV mechanical dyssynchrony pattern, characterized by ApRock and SF, is associated with a more favourable long-term survival after CRT. Both parameters are also indicators of an effective therapy. [10.1093/ehjci/jev324][1] [1]: /lookup/doi/10.1093/ehjci/jev324

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. ispartof: TRANSPLANTATION DIRECT vol:4 issue:5 ispartof: location:United States status: published

OBJECTIVES The aim of this study was to compare the volumetric response and the long- term survival after cardiac resynchronization therapy (CRT) in patients with intrinsic left bundle branch block (LBBB) versus chronic right ventricular pacing (RVP) with respect to the presence of mechanical dyssynchrony (MD). BACKGROUND Chronic RVP induces an iatrogenic LBBB and asynchronous left ventricular contraction that is potentially reversible by upgrading to CRT. METHODS A total of 914 patients eligible for CRT (117 with conventional pacemakers and 797 with intrinsic LBBB) were included in the study. MD was visually assessed before CRT and was defined as the presence of either apical rocking and/or septal flash on baseline echocardiograms. Patients with a left ventricular end-systolic volume decrease of >= 15% during the follow-up were considered responders. Patients were followed for all-cause mortality during the median follow-up of 48 months (interquartile range: 29 to 66 months). RESULTS MDwas observed in 51% of patientswithRVP versus 77% in patients with intrinsic LBBB( p< 0.001). Patients with RVP and MD had a similar likelihood of volumetric response as did patients with intrinsic LBBB and MD (adjusted odds ratio: 0.71; 95% confidence interval: 0.33 to 1.53; p - 0.385). There was no significant difference in long-term survival between patients with RVP and intrinsic LBBB (adjusted hazard ratio: 1.101; 95% confidence interval: 0.658 to 1.842; p = 0.714). Patients with visual MD and either intrinsic LBBB or RVP had a more favorable survival than those without MD (p < 0.001). CONCLUSIONS The likelihood of volumetric response and a favorable long-term survival of patients with RVP was similar to those of patients with intrinsic LBBB and were mainly determined by the presence of MD and not by the nature of LBBB. (C) 2017 by the American College of Cardiology Foundation.

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.

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 postimplantation. 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

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. ispartof: JOURNAL OF CLINICAL MEDICINE vol:8 issue:9 ispartof: location:Switzerland status: published

Introduction: Numerous cohort analyses suggest rapidly increasing use of mechanical circulatory support (MCS) as a bridge to heart transplantation (HTx), but the role of age in selection for MCS remains unknown. Methods: We assessed adult HTx in the International Society for Heart And Lung Transplantation Registry between 2005 and 2013 and we determined MCS use by recipient age group and transplant year. Multivariable logistic regression models were constructed to identify variables associated with continuous flow (CF) left ventricular assist device (LVAD) use within each age group. Results: Among 16,480 HTx recipients the percentage of overall MCS use increased from 23% to 38%, 21% to 41%, and 17% to 42% in age groups 18-39 years, 40-59 years and over 60 years, respectively. This effect was mainly due to an increase in CF LVAD use and primarily in HTx recipients aged over 60. In multivariable analyses, male gender and blood group O were significantly associated with CF LVAD use in all agegroups. Conclusions: Bridge to transplant MCS use increased dramatically between 2005 and 2013 primarily due to increased use of CF LVAD and primarily in higher ages. Pre-HTx CF LVAD use was more frequent in men and blood group O. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Heart transplantation (HT) recipients may have tachycardia secondary to cardiac denervation. As higher heart rate predicts worse outcomes in cardiovascular disease, we hypothesized that tachycardia and nonuse of β blockers are associated with increased mortality after HT. All patients who underwent HT at our institution from 1987 to 2010 were included. The association of heart rate 3 months after HT and β-blocker use during follow-up to mortality was assessed using Kaplan-Meier and multivariate Cox proportional hazards regression analyses adjusting for clinically relevant baseline variables. From 1987 to 2010, there were 493 HT. After excluding 29 who died within 3 months and 3 with follow-up3 months, 461 HT recipients (50 ± 2 years; 20% women) were included. Over a follow-up of 12 ± 7 years, selected important univariate predictors of post-HT mortality were older age, male gender, higher body mass index, ischemic cardiomyopathy, longer post-HT intensive care unit stay, and hospitalization and at 3 months, increased mean pulmonary artery pressure, right atrial pressure and pulmonary capillary occlusion pressure, higher heart rate, and nonuse of β blockers during follow-up. In multivariate analysis, older ager, longer hospitalization, higher mean pulmonary artery pressure, higher heart rate at 3 months (hazard ratio 1.02 per beat, 95% confidence interval 1.008 to 1.035, p = 0.02) and nonuse of β blockers (hazard ratio 1.43, 95% confidence interval 1.002 to 2.031, p0.05) were associated with mortality. In conclusion, in a large single-center cohort of HT recipients, higher heart rate and nonuse of β blockers were independently associated with higher mortality.

Aims In some pulmonary hypertension (PH) patients, we noted a motion pattern where the right ventricular (RV) apex is pulled towards to left ventricle (LV) during systole, caused by traction from the LV (‘apical traction’, AT). Herein, we characterize patients with AT to investigate its prognostic significance. Methods and results Echocardiograms of 62 pre-capillary PH patients (42 females, age 61 ± 15 years) were retrospectively analysed. The presence of AT was assessed visually and confirmed by speckle-tracking analysis. Fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV free-wall longitudinal strain (LS) as well as LV function were measured. A primary end point of death or heart/lung transplantation was set. AT was observed in 31 patients. They had worse functional capacity, lower TAPSE (1.3 ± 0.2 vs. 1.9 ± 0.4, P ≤ 0.001) and FAC (20.3 ± 6.1 vs. 33 ± 7.1%, P ≤ 0.001), worse RV free-wall LS (−12.4 ± 3.4 vs. −20.8 ± 4.9%, P < 0.001), and higher systolic pulmonary arterial pressure (92 ± 15 vs. 75 ± 23, P < 0.001). LV function was similar in both groups. The primary end point occurred in 16 patients with and 8 without AT. AT was an independent predictor of the outcome (HR: 14.826, 95% CI: 1.696−129.642, P = 0.015). Conclusion AT occurs in RVs with impaired systolic function in PH patients. It may serve as a new, easily to assess visual parameter to predict the outcome in these patients. Its prognostic importance needs to be validated by prospective studies.

Background— Heart failure is characterized by increased ventilation during exercise, which is positively related to increased peripheral and central chemoreceptor sensitivity. Heart transplantation does not normalize the ventilatory response to exercise, and its effects on the chemoreflex control of ventilation remain unknown. We tested the hypothesis that chemoreceptor sensitivity is increased in heart transplant recipients (HTRs) and linked to exercise hyperpnea. Methods and Results— We determined the ventilatory, muscle sympathetic nerve activity (MSNA), and circulatory responses to isocapnic hypoxia and hyperoxic hypercapnia 7±1 years after transplantation in 19 HTRs with a normal left ventricular ejection fraction of 60±2%. Results were compared with those of 11 closely matched referent subjects. Sixteen patients and 10 referent subjects also underwent cycle ergometer exercise tests. HTRs compared with referent subjects presented higher MSNA (52±4 versus 34±3 bursts/min; P P P P 2 output, was steeper in HTRs than in referent subjects (38±2 versus 29±1 L/mm Hg; P r =0.57; n=16; P r =0.50; n=16; P Conclusions— Peripheral chemoreceptor sensitivity is increased in HTRs and is related to exercise hyperpnea after heart transplantation.

ObjectiveIncreased arterial stiffness is a determinant of cardiovascular mortality. Pulse wave velocity (PWV) is a direct measure of arterial stiffness. Aortic augmentation index (AI) and pulse pressure (PP) are surrogate measures of arterial stiffness. Both PWV, AI and PP increase with cardiovascul

Transcatheter aortic valve implantation (TAVI) is becoming a valuable alternative to surgical aortic valve replacement in non-operable and high-risk surgical patients. As the population of heart donors and recipients ages, the prevalence of degenerative valvular disease after transplantation will increase. The optimal treatment strategy of valvulopathies in these patients with extensive comorbidity is still unknown because of insufficient published experience. We present a heart transplant recipient with renal failure, systolic heart failure and severe aortic stenosis who was successfully treated with transapical TAVI.

Carotid chemoreceptors provoke an increase in muscle sympathetic nerve activation (MSNA) in response to hypoxia; they are also tonically active during normoxic breathing. The contribution of peripheral chemoreceptors to sympathetic activation in hypertension is incompletely understood. The aim of our study was to investigate the effect of chemoreceptor deactivation on sympathetic activity in untreated patients with hypertension. A total of 12 untreated hypertensive males and 11 male controls participated in this randomized, crossover, placebo-controlled study. MSNA, systolic blood pressure(BP), diastolic BP, heart rate (HR), electrocardiogram, hemoglobin oxygen saturation (Sat%) and respiratory movements were measured during repeated 10-min periods of respiration with 100% oxygen or 21% oxygen in a blinded fashion. Compared with controls, hypertensives had higher resting MSNA (38 ± 10 vs. 29 ± 0.9 burst per min, P

Multidetector computed tomography angiography (CTA) provides information on plaque extent and stenosis in the coronary wall. More accurate lesion assessment may be feasible with CTA as compared to invasive coronary angiography (ICA). Accordingly, lesion length assessment was compared between ICA and CTA in patients referred for CTA who underwent subsequent percutaneous coronary intervention (PCI). 89 patients clinically referred for CTA were subsequently referred for ICA and PCI. On CTA, lesion length was measured from the proximal to the distal shoulder of the plaque. Quantitative coronary angiography (QCA) was performed to analyze lesion length. Stent length was recorded for each lesion. In total, 119 lesions were retrospectively identified. Mean lesion length on CTA was 21.4 ± 8.4 mm and on QCA 12.6 ± 6.1 mm. Mean stent length deployed was 17.4 ± 5.3 mm. Lesion length on CTA was significantly longer than on QCA (difference 8.8 ± 6.7 mm, P < 0.001). Moreover, lesion length visualized on CTA was also significantly longer than mean stent length (CTA lesion length-stent length was 4.2 ± 8.7 mm, P < 0.001). Lesion length assessed by CTA is longer than that assessed by ICA. Possibly, CTA provides more accurate lesion length assessment than ICA and may facilitate improved guidance of percutaneous treatment of coronary lesions.

Objective: Nonischemic dilated cardiomyopathy with functional mitral regurgitation carries a poor prognosis. Mitral valve surgery with implantation of a cardiac support device can treat mitral regurgitation and promote left ventricular reverse remodeling. This observational study evaluates clinical and echocardiographic outcomes of an individualized medico-surgical approach, focusing on mitral regurgitation recurrence and left ventricular reverse remodeling. Methods: Sixty-nine consecutive patients with heart failure (New York Heart Association class III/IV) with functional mitral regurgitation (grade 3+/4+) and left ventricular remodeling (end-diastolic volume 227 +/- 73 mL, ejection fraction 26% +/- 8%) underwent restrictive mitral annuloplasty (median ring size 26), with (n = 41) or without (n 28) a cardiac support device and optimal postoperative medical treatment. Patients were clinically and echocardiographically evaluated at up to 3.1 years' median follow-up. Results: Early mortality was 5.8%. Actuarial survival at 1, 2, and 5 years was 86% +/- 4%, 79% +/- 5%, and 63% +/- 7%. New York Heart Association class improved from 3.1 +/- 0.4 to 2.0 +/- 0.5 (P

The origin of mitral regurgitation (MR), independent of the lesion type, lies in reduced coaptation between the valve leaflets which normally assure mitral valve competence. The European Society of Cardiology (ESC) has issued guidelines that classify this disorder as either primary (organic) or secondary (ischaemic and functional) MR.1 In primary MR it is the valve itself which is at the origin of the problems, while in the case of secondary MR, it is the left ventricle (LV) that has sustained previous damage due to a myocardial infarction or dilated cardiomyopathy, resulting in annular dilatation and lateral displacement of the papillary muscles causing mitral valve insufficiency.1 Ischaemic MR results from a restriction of the mitral leaflets due to tethering of the subvalvular apparatus in an LV affected by ischaemia, while functional MR is secondary to changes in LV geometry resulting from LV dysfunction (as observed in idiopathic or ischaemic cardiomyopathy with severe LV dysfunction).1 Treatments and surgical indications vary considerably between those with primary and secondary MR. However, different existing classifications of MR according to mechanisms, causes, and mitral leaflet motion can nevertheless be a potential source of confusion due to overlapping terminology (table 1).w1 MR can be divided into primary and secondary types (as proposed by ESC guidelines) and can be further subclassified based on the leaflets' movement (Carpentier's classification, figure 1) or the causes of cardiomyopathy (table 1). Secondary MR can be both ischaemic or non-ischaemic in nature and can be characterised by a normal movement of the leaflets with annular dilatation (Carpentier type I) or systolic restriction and tethering of the mitral leaflets secondary to LV dysfunction (Carpentier type IIIb). View this table: Table 1 Causes and mechanisms of mitral regurgitation Figure 1 Carpentier classification of mitral regurgitation (MR). Mechanisms causing MR are schematically depicted in the upper row and …

s S15 Conclusion: This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.

Restrictive mitral annuloplasty is a surgical treatment option for patients with heart failure (HF) and functional mitral regurgitation (MR). However, recurrent MR has been reported at mid-term follow-up. The aim of the present study was to identify the echocardiographic predictors of recurrent MR in patients with HF undergoing mitral annuloplasty. During a mean follow-up of 2.6 +/- 1.6 years, 109 patients with HF (49% ischemic and 51% idiopathic dilated cardiomyopathy) who had undergone mitral valve repair were followed up (of 122 total patients). The severity of MR was quantified, and the following parameters were measured before intervention and at the mid-term follow-up examination: left ventricular (LV) and left atrial volumes and dimensions, LV sphericity index, mitral annular area, and mitral valve geometry parameters. At mid-term follow-up, 21 patients presented with significant MR (grade 2 to 4), and 88 patients had only MR grade 0 to 1. Both groups of patients had had a similar preoperative MR grade, mitral annular area, and LV volume and dimension. In contrast, patients with recurrent MR had had increased preoperative posterior and anterior leaflet angles, tenting height, tenting area, and LV sphericity index compared to the patients without recurrent MR. Of the different parameters of mitral and LV geometry, the distal mitral anterior leaflet angle (hazard ratio 1.48, 95% confidence interval 1.32 to 1.66, p

Beyond their hypolipidemic effect, statins reduce cardiovascular risk in hypertensive subjects via various mechanisms; one suggested mechanism is that they reduce sympathetic activity. We investigated the hypothesis that simvastatin decreased muscle sympathetic nerve activity (MSNA) in 31 hypertensive subjects with hypercholesterolemia (aged 38.7 ± 10 years). In this randomized, placebo-controlled, double-blinded study, patients were treated with simvastatin (40 mg day(-1); n=15) or placebo (n=16) for 8 weeks. Before and after treatment, we measured MSNA, blood pressure and heart rate. Baroreceptor control of the heart rate, or baroreceptor sensitivity (BRS), was computed by the sequence method, a cross-analysis of systolic blood pressure and the electrocardiogram R-R interval. Blood samples were tested for plasma levels of catecholamines, neuropeptide Y, aldosterone, endothelin and renin activity. Simvastatin significantly reduced MSNA (from 36.5 ± 5 to 27.8 ± 6 bursts per min, P=0.001), heart rate (from 77 ± 6.7 to 71 ± 6.1 beats per min, P=0.01) and both total and low-density lipoprotein cholesterol (from 249 ± 30.6 to 184 ± 28.3 mg dl(-1), P=0.001 and from 169 ± 30.6 to 117 ± 31.2 mg dl(-1), P=0.01, respectively). Simvastatin also improved BRS (from 10.3 ± 4.1 to 17.1 ± 4.3 ms per mm Hg, P=0.04). No changes were observed in systolic or diastolic blood pressures, or in plasma levels of catecholamines, neuropeptide Y, endothelin, aldosterone and renin activity. After simvastatin therapy, MSNA and BRS were inversely related (r=-0.94, P0.05). In conclusion, we found that, in patients with hypertension and hypercholesterolemia, simvastatin reduced MSNA, and this was related to increased baroreceptor sensitivity.

The sympathetic nervous system has been reported to be activated in pulmonary arterial hypertension (PAH).We investigated the prognostic significance of muscle sympathetic nervous system activity (MSNA) in PAH.Thirty-two patients with PAH were included in the study and underwent a measurement of MSNA over a 6-year period of time. They had undergone a concomitant evaluation of New York Heart Association (NYHA) functional class, a 6-minute walk distance (6MWD), an echocardiographic examination, and a right heart catheterization for diagnostic or reevaluation purposes. The median follow-up time was 20.6 months (interquartile range, 45.8 mo). Clinical deterioration was defined by listing for transplantation or death.Seventeen patients presented with clinical deterioration. As compared with the 15 others, they had an increased MSNA (80 +/- 12 vs. 52 +/- 18 bursts/min; P0.001) and heart rate (88 +/- 17 vs. 74 +/- 12 bpm; P = 0.01), a lower 6MWD (324 +/- 119 vs. 434 +/- 88 m; P0.01) and a deteriorated NYHA functional class (3.6 +/- 0.5 vs. 2.9 +/- 0.8; P0.001). The hemodynamic variables were not different. MSNA was directly related to heart rate and inversely to 6MWD. A univariate analysis revealed that increased MSNA and heart rate, NYHA class IV, lower 6MWD, and pericardial effusion were associated with subsequent clinical deterioration. A multivariate analysis showed that MSNA was an independent predictor of clinical deterioration. For every increase of 1 burst/minute, the risk of clinical deterioration during follow-up increased by 6%.Sympathetic nervous system activation is an independent predictor of clinical deterioration in pulmonary arterial hypertension.

[Figure][1] ![Figure][1] [Video 1][2] Coronary Angiography The left coronary artery connected to the right coronary artery. ![Figure][1] [Video 2][3] Abnormal Flow in the Left Ventricular Outflow Tract Transthoracic echocardiography, parasternal long-axis view. In blue

Increased sympathetic activity might be related to pathogenesis of hypertension as well as to end organ damage. Animal studies suggest that statins decrease sympathetic activity and increase baroreceptor reflex sensitivity (BRS).To examine whether atorvastatin decreases muscle sympathetic nerve activity (MSNA) and BRS in hypercholesterolaemic and hypertensive patients.Ten patients with essential hypertension and untreated hypercholesterolaemia (aged 43 +/- 12 years) and eight healthy subjects (aged 37 +/- 7 years) were enrolled in the study. In both groups the recordings of microneurography, ECG, blood pressure and BRS were performed twice, before and after 8 weeks during which the patients (but not controls) were treated with atorvastatin.Compared with controls, the patients had higher MSNA values (36.0 +/- 6.6 vs. 29.8 +/- 3.7 bursts/minute), mean BP levels (145.1 +/- 10 vs. 124.1 +/- 11.1 mmHg) and total cholesterol concentration (252.6 +/- 22.6 vs. 179.8 +/- 20.7 mg/dl) baseline values. Statin therapy resulted in a decrease of total cholesterol (252.6 +/- 22.0 vs. 173.8 +/- 26.2 mg/dl, p0.05) and MSNA (36.0 +/- 6.6 vs. 28.6 +/- 4.8 bursts/min, p0.05), whereas BRS values were increased (12.6 +/- 5.6 vs. 18.1 +/- 5.9 ms/mmHg, p0.05). Post-treatment BRS was inversely related to post-treatment MSNA (r = -0.73, p0.05). In the controls there were no changes in MSNA (29.8 +/- 3.7 vs. 28.9 +/- 2.9 bursts/min), BRS (11.9 +/- 5.0 vs. 13.1 +/- 4.8 ms/mmHg), total cholesterol, BP and heart rate between the first and the second measurement.Atorvastatin reduces MSNA and increases BRS in hypertensive and hypercholesterolaemic patients. Decrease in sympathetic activity may be the result of improvement of baroreceptor function by atorvastatin.

Purpose: Exercise-induced dyspnea in patients with cardiopulmonary diseases may be related to sympathetic nervous system activation, with increased metabo- and/or chemosensitivities. Whether this mechanism plays a role in exercising normal subjects remains unclear. Methods: Muscle sympathetic nerve activity (MSNA), HR, ventilation (V[spacing dot above]E), O2 saturation (SpO2), and end-tidal PCO2 (PetCO2) were measured in 14 healthy young adults after 1 wk of [beta]1-receptor blockade with bisoprolol 5 mg[middle dot]d-1 versus placebo after a double-blind, placebo-controlled, randomized crossover design. The MSNA and the ventilatory responses to hyperoxic hypercapnia (7% CO2 in O2), [DELTA]V[spacing dot above]E/[DELTA]PetCO2, and isocapnic hypoxia (10% O2 in N2), [DELTA]V[spacing dot above]E/[DELTA]SpO2, and to an isometric muscle contraction followed by a local circulatory arrest (metaboreflex) were determined at rest followed by an incremental cardiopulmonary exercise test. Results: Bisoprolol did not change the V[spacing dot above]E and MSNA responses to hypercapnia, hyperoxia, or isometric muscle contraction or ischemia. Bisoprolol decreased maximum O2 uptake (P < 0.05), workload (P < 0.05), and HR (P < 0.0001) andboth V[spacing dot above]E/V[spacing dot above]O2 and V[spacing dot above]E/V[spacing dot above]CO2 slopes (P < 0.05). Conclusions: These results suggest that decreased aerobic exercise capacity after intake of [beta]-blockers is accompanied by decreased ventilation at any metabolic rate. However, this occurs without detectable change in the sympathetic nervous system tone or in metabo- or chemosensitivity and is therefore probably of hemodynamic origin.

International audience; BACKGROUND: Myocardial infarction (MI) is a leading cause of death among adults and MI survivors have increased risk of developing heart failure. MI is accompanied by acute sympathetic nervous system activation, which becomes persistent in heart failure patients. OBJECTIVE: We establish whether current and investigated therapies affect sympathetic activation after MI and in heart failure patients. METHODS: We reviewed the literature on the mechanisms of sympathetic nervous system activation and effects of standard and investigated treatments on adrenergic activation after MI and in heart failure patients. RESULTS/CONCLUSION: Angioplasty and beta-blockers result in a decrease of adrenergic activation after acute MI; in heart failure patients, medications that affect renin-angiotensin-aldosterone system modulate sympathetic activation. Endothelin receptors agonists, adenosine receptors antagonists, arginine vasopressin antagonists, cardiac myosin activators, natriuretic peptide analogues, vasopeptide inhibitors, renin inhibitors, tyrosine kinase inhibitors and dopamine receptors inhibitors were tested in heart failure settings. They target better management of neurohumoral activation.

Heart transplantation does not normalize exercise capacity or the ventilatory response to exercise. We hypothesized that excessive muscle reflex activity, as assessed by the muscle sympathetic nerve activity (MSNA) response to handgrip exercise, persists after cardiac transplantation and that this mechanism is related to exercise hyperpnea in heart transplant recipients (HTRs). We determined the MSNA, ventilatory, and cardiovascular responses to isometric and dynamic handgrips in 11 HTRs and 10 matched control subjects. Handgrips were followed by a post-handgrip ischemia to isolate the metaboreflex contribution to exercise responses. HTRs and control subjects also underwent recordings during isocapnic hypoxia and a maximal, symptom-limited, cycle ergometer exercise test. HTRs had higher resting MSNA ( P < 0.01) and heart rate ( P < 0.01) than the control subjects. Isometric handgrip increased MSNA in HTRs more than in the controls ( P = 0.003). Dynamic handgrip increased MSNA only in HTRs. During post-handgrip ischemia, MSNA and ventilation remained more elevated in HTRs ( P < 0.05). The MSNA and ventilatory responses to hypoxia were also higher in HTRs (both P < 0.04). In HTRs, metaboreflex overactivity was related to the ventilatory response to exercise, characterized by the regression slope relating ventilation to CO2 output ( r = +0.8; P < 0.05) and a lower peak ventilation ( r = +0.81; P < 0.05) during cycle ergometer exercise tests. However, increased chemoreflex sensitivity ( r = +0.91; P < 0.005), but not metaboreflex activity, accounted for the lower peak ventilation during exercise in a stepwise regression analysis. In conclusion, heart transplantation does not normalize muscle metaboreceptor activity; both increased metaboreflex and chemoreflex control are related to exercise intolerance in HTRs.

Dopamine (DA) is an immediate precursor of noradrenaline that has stimulatory or inhibitory effects on a variety of adrenergic receptors. DA is primarily used in the management of circulatory shock for its combined vasopressor and inotropic effects, but it may also exert significant effects on the respiratory system Although the respiratory effects of intravenous DA attract less attention than its hemodynamic effects, there is evidence that DA affects ventilation, pulmonary circulation, bronchial diameter, neuromodulation of sensory pulmonary nerves and lung water clearance. Through these complex mechanisms, DA may exert beneficial as well as detrimental effects on respiration. DA may have beneficial effects on the respiratory system by decreasing oedema formation and improving respiratory muscle function, but can also have deleterious effects, by inhibiting ventilation. Hence, DA may be beneficial in lung oedema, but harmful in cases of difficult weaning from mechanical ventilation. DA should be used with caution in patients with heart failure during weaning from mechanical respiration; however, critically ill patients with chronic obstructive pulmonary disease (COPD) do not show this negative effect of DA on ventilatory drive.