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Introduction: Patients(pts) with paroxysmal atrial fibrillation are at risk for developing heart failure with preserved ejection fraction(HFpEF) and often have an impaired exercise capacity. Since left atrial (LA) pressure plays a major role in the exercise intolerance, we aimed to characterize the contribution of resting LA mechanical properties, assessed by two-dimensional speckle tracking echocardiography upon exercise capacity. Purpose: To evaluate relationship between LA mechanics, measured by LA strain (LAS) and parameters of exercise capacity in pts with paroxysmal atrial fibrillation. Methods: The study included 54 pts(64 ± 10years, 76 % males) with dyspnea (NYHA³II), paroxysmal atrial fibrillation and preserved LV ejection fraction (≥50%). The likelihood of HFpEF was estimated using H2FPEF score. During sinus rhythm, all patients underwent speckle tracking echocardiography and cardiopulmonary exercise testing (CPET). Peak oxygen uptake(VO2peak) served as measure of functional capacity and ventilation/carbon dioxide output slope(VE/VCO2) as surrogate of ventilation/perfusion mismatch. Results: LA contractile strain(S) and strain rate(SR) showed significant correlation with VO2peak(both p < 0.05). LA reservoir, conduit and contractile LAS, all had significant relationship with VE/VCO2 slope (all pConclusions: In HFpEF VO2peak and VE/VCO2 are closely related to LA contractile strain, suggesting that abnormalities in LA mechanics may contribute to the blunted exercise capacity. Therefore, we speculate that these markers can be used as an echocardiographic surrogate of functional capacity in HFpEF pts. Further studies are warranted.

Introduction: Heart failure (HF) is a heterogenous syndrome with complex pathophysiology. Biomarkers and clinical risk scores often fail to capture modifications in the treatment continuity and provide suboptimal patient-level precision in the prognostic stratification. Electronic patient records provide necessary granularity yielding opportunities to develop new artificial intelligence (AI) based strategies for comprehensive prognostic re-stratification. Hypothesis: We assessed the hypothesis that, utilizing longitudinal patient data in an AI approach, yields superior performance predicting all-cause mortality in a cohort of patients hospitalized with a de novo or worsened HF, compared to single observational time point predictions. Methods: In a cohort of 2449 HF patients hospitalized between 2011-2017, we utilized 151 451 patient exams from 422 parameters. Features included clinical phenotyping, medication, ECG, laboratory, echocardiography, catheterization data or percutaneous and surgical interventions gathered on a routine clinical basis reflecting standard of care as captured in individual electronic records. AI models were developed, and their performance on the validation set was compared to industry standard clinical scores. Results: AI models yielded performance ranging from 0.83 to 0.89 AUC on the outcome-balanced validation set in predicting all-cause mortality at 30-, 90-, 180-, 360- and 720-day time-limits. The primary endpoint, 1-year mortality prediction model, recorded 0.85 AUC on the validation set compared to 0.7 AUC (Seattle HF model) and 0.73 AUC (MAGGIC HF Score) respectively. Conclusions: Our findings present a novel, patient-level, AI-based risk prediction approach of all-cause mortality in heart failure utilizing all historical data available in electronic health records. This suggests the potential of AI based predictive models in a point-of-care approach to guide clinical risk stratification.

Introduction: Overexpression of serpin peptidase inhibitor, clade A member 3 (SERPINA3) has been associated with poor prognosis in cancer. Hypothesis: SERPINA3 in a de novo or worsened heart failure (HF) bears a prognostic information alone and in addition to established biomarkers NT-proBNP and ST2 or clinical risk factors. Methods: Circulating SERPINA3 levels were examined in HFpatients who died within 5 years (n=44) and compared with age- and hemodynamically matched survivors (n=39). Prognostic value of circulating SERPINA3 levels alone and in combination with ST2 and NT-proBNP was then analyzed in an independent cohort with a de novo or worsened HF (n=384). Results: Plasma SERPINA3 levels were significantly higher in HF non-survivors compared to survivors (334.7 ± 138.7 vs 228.2 ± 83.1 μg/mL, pde novo or worsened HF (n=384), circulating SERPINA3 levels >316 μg/mL were associated with increased all-cause mortality (HR (95% CI): 2.4 (1.5-3.9), p=0.0002) and its composite with unplanned cardiac admission (HR (95% CI): 2.0 (1.2-3.3), p=0.004). In a multivariate analysis, including established clinical risk factors and ST2 and NT-proBNP, SERPINA3 remained independent predictor of all-cause mortality together with age, ST2, glomerular filtration and pulmonary capillary wedge pressure. Conclusions: Elevated SERPINA3 appears to provide additional prognostic information in models incorporating clinical, hemodynamic and laboratory risk including ST2 and NT-proBNP by identifying a subgroup of heart failure patients at increased mortality risk.

AIMS: We investigated the prognostic relevance of serpin peptidase inhibitor, clade A member 3 (SERPINA3) in patients admitted with a de novo or worsened heart failure (HF). METHODS AND RESULTS: In the first stage, 83 HF-related left ventricular (LV) transcripts were examined in patients with congestive cardiomyopathy (CCMP, n = 44) who died within 5 years and compared with age-matched and haemodynamically matched CCMP survivors (n = 39) and controls with normal LV function (n = 17). Among 14 differentially expressed transcripts, myocardial gene and circulating SERPINA3 levels were up-regulated in non-survivors vs. survivors (2.40 ± 3.66 vs. 0.36 ± 0.22 units, P 316 μg/mL were associated with increased all-cause mortality {hazard ratio [HR] [95% confidence interval (CI)]: 2.4 [1.5-3.9], P = 0.0002} and its composite with unplanned cardiovascular readmission [HR (95% CI): 2.0 (1.2-3.3), P = 0.004]. Patients with elevated SERPINA3 levels and elevated either N-terminal pro brain natriuretic peptide or ST2 showed worse freedom from both endpoints. In a multivariate analysis, including established clinical risk factors, SERPINA3 remained independent predictor of all-cause mortality together with age, gender, ST2, glomerular filtration, and pulmonary capillary wedge pressure. CONCLUSION: In patients with a de novo or worsened HF, increased SERPINA3 levels > 316 μg/mL are associated with increased mortality or unplanned cardiac readmission. Elevated SERPINA3 levels on top of established clinical predictors appear to identify a subgroup of HF patients at higher mortality risk. Prospective studies should further validate its value in prognostic stratification of HF. ispartof: ESC HEART FAILURE vol:8 issue:6 ispartof: location:England status: published

Background Heart failure (HF) is a heterogenous syndrome with complex pathophysiology. Biomarkers and clinical risk scores often fail to provide optimal patient-level precision in the prognostic stratification. As utilizing single observational timepoint, they do not capture the entire care pathway with variations in individual patient management. Electronic patient records provide an opportunity to develop new artificial intelligence (AI) strategies for comprehensive prognostic re-stratification reflecting diagnostic and therapeutic management. Purpose We sought to use deep artificial intelligence (AI) and develop an unbiased predictive algorithm for all-cause mortality in a cohort of patients hospitalized with a de novo or worsened HF. Methods In a cohort of 2449 HF patients hospitalized between 2011–2017, we utilized 151 451 patient exams from 422 parameters. They included clinical phenotyping, medication, ECG, laboratory, echocardiography, catheterization data or percutaneous and surgical interventions gathered on a routine clinical basis reflecting standard of care as captured in individual electronic records. The AI model development consisted of 101 iterations of repeated random subsampling splits into balanced training and validation sets. Results AI models yielded performance ranging from 0.83 to 0.89 AUC on the outcome-balanced validation set in predicting all-cause mortality at 30-, 90-, 180-, 360- and 720-day time-limits (Figure 1). The primary endpoint, 1-year mortality prediction model, recorded an 0.85 AUC accuracy. We observed stable model performance across all HF phenotypes: HFpEF 0.83 AUC, HFmrEF 0.85 AUC and HFrEF 0.86 AUC, respectively). Conclusion Our findings present a novel, patient-level, AI-based risk prediction of all-cause mortality in heart failure with a robust accuracy across its phenotypes. This suggests the potential of AI based predictive models in a point-of-care approach to guide clinical risk stratification. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): VZW Cardiovascular Research Center Aalst

The additional role of continuous monitoring of filling pressures and impedance in heart failure patients with chronic kidney disease remains undetermined. In this case report, the effects of diuretic therapy and renal replacement therapy by hemodialysis upon right ventricular filling pressures and impedance are described in a patient with end-stage heart failure and end-stage chronic kidney disease (grade 5). We demonstrated that unloading of the heart by hemodialysis partly restored the blunted Frank-Starling relationship.

Introduction Breast cancer patients receiving anthracyclines are particularly prone to develop cancer therapeutics-related cardiac dysfunction. Early detection of cardiotoxicity onset is required for optimal timing of cardio protection treatment. The latest guidelines consider a relative reduction of 15% in global longitudinal strain (GLS) from baseline as risk for cardiotoxicity. Nevertheless, the more recent Myocardial Work Index (MWI) offers a load-independent tool for detection of subclinical heart failure (HF). However, data in cancer patients are still scarce. Purpose This study analyses the predictive value of MWI for cardiotoxicity diagnosis after 6 months chemotherapy. Methods The study population consists of breast cancer patients referred for chemotherapy with anthracyclines and taxanes. Patients with a history of HF previous to chemotherapy or depressed LV function at baseline were excluded. Echocardiography was performed before onset of the chemotherapy (baseline) and after 6 months follow-up. LVEF, GLS and MWI were assessed offline using EchoPAC software. The values at baseline and 6 months follow-up were pairwise compared to detect subclinical cardiac dysfunction. LVEF, GLS and MWI means at baseline were taken as cut-off to compare the predictive value of each parameter. Moreover, patients were categorized in one group with GLS reduction >15% (Group 1) and one group with GLS reduction Results From April 2016 to July 2020, 28 women with breast cancer were included (age 54±11 years, LVEF 58±4%, GLS −21±2%, MWI 2160±308 mmHg). All patients underwent the same standard chemotherapy protocol (4xEC, 12xTaxol). No difference in baseline characteristics between group 1 (n=13) and group 2 (n=15) was observed. At 6 months follow up a significant decrease in LVEF (53±8%, p=0.003), GLS (−19±3%, p=0.002) and MWI (1920±391 mmHg, p=0.005) was shown without any change in blood pressure. However, while mean LVEF and GLS at baseline did not predict any significant change, patients with MWI under the mean value at baseline (n=15) presented significant lower LVEF (50±8 vs 57±6% p=0.006), GLS (−17±3 vs −20±2%, p=0.01), MWI (1733±320 vs 2136±362 mmHg, p=0.005) after 6 months. Additionally, both groups had similar MWI at baseline (2148±335 mmHg vs 2170±294 mmHg, p=0.85), whereas those patients with GLS reduction >15% showed significant lower MWI after 6 months (1694±332 mmHg vs 2116±334 mmHg, p=0.003, Figure 1). Conclusions At 6 months follow up, a decline of the LV systolic function as side effect of chemotherapy can be seen. MWI at baseline shows the best predictive value for development of cardiotoxicity, in comparison to LVEF and GLS. Further studies are warranted to better understand the role of MWI for early detection of cardiotoxicity and its clinical relevance. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Onze-Lieve-Vrouw hospital in Aalst (Belgium)

Cardiac transplant-related vasculopathy remains a leading cause of morbidity and mortality in heart transplant (HTx) recipients. Recently, coronary angiography-derived vessel fractional flow reserve (vFFR) has emerged as a new diagnostic computational tool to functionally evaluate the severity of coronary artery disease. Although vFFR estimates have been shown to perform well against invasive FFR in atherosclerotic coronary artery disease, data on the use of vFFR in heart transplant recipients suffering from cardiac transplant-related arteriopathy are lacking. The aim of the presented study was to validate coronary angiography-derived vessel fractional flow reserve to calculate fractional flow reserve in HTx patients with and without cardiac transplant-related vasculopathy. A prospective, single center study of HTx patients referred for annual check-up, undergoing surveillance coronarography was conducted. Invasive FFR was measured using a motorized device at the speed of 1.0 mm/s in all three major coronary arteries. Angiography-derived pullback FFR was derived from the angiogram and compared with invasive FFR pullback curve. Overall, 18,059 FFR values were extracted from the FFR pullback curves from 23 HTx patients. The mean age was 59.3 ± 9.7 years, the mean time after transplantation was 5.24 years [IQR 1.20, 11.25]. A total of 39 vessels from 23 patients (24 LAD, 11 LCX, 4 RCA) were analyzed. Mean distal vFFR was 0.87 ± 0.14 whereas invasive distal FFR was 0.88 ± 0.17. An excellent correlation was found between invasive distal FFR and vFFR (r = 0.92; p < 0.001). The correlation of the pullback tracing was high, with a correlation coefficient between vFFR and invasive FFR pullback values of 0.72 (95% CI 0.71 to 0.73, p < 0.001). The mean difference between vFFR and invasive FFR pullback values was -0.01 with 0.06 of SD (limits of agreements -0.12 to 0.13). In HTx patients, coronary angiography-derived FFR correlates excellently with invasively measured wire-derived FFR. Therefore, angiography derived FFR could be used as a novel diagnostic tool to quantify the functional severity of graft vasculopathy. ispartof: DIAGNOSTICS vol:11 issue:10 ispartof: location:Switzerland status: published

This study aimed to examine the relationship between corin expression and circulating brain natriuretic peptide in patients with left ventricular (LV) dysfunction.Circulating levels of B-type natriuretic peptide (BNP) can be an indicator of LV dysfunction. The 32-amino-acid BNP is cleaved by corin, a cardiac serine protease, from its108-amino-acid pro-brain natriuretic peptide (proBNP) precursor.This study included 25 patients with idiopathic dilated cardiomyopathy (DCMP) and LV dysfunction and 44 heart transplant recipients with normal LV function who underwent diagnostic left and right heart catheterization. Blood samples were used to determine the ratio of plasma proBNP/BNP levels, and LV endomyocardial biopsies were used to determine the expression of NPPB, which encode BNP and corin, respectively, by quantitative reverse transcription-polymerase chain reaction.Patients with DCMP revealed worse hemodynamic profiles and higher plasma proBNP and BNP levels than those of the transplant recipients. Myocardial NPPB expression was higher and CORIN expression was lower in the DCMP patients than in the transplant recipients. CORIN expression significantly correlated with NPPB expression (r = -0.585; P < 0.001), ejection fraction (EF; r = 0.694; P < 0.01), LV end-diastolic pressure (r = -0.373; P < 0.05), and indexed end-diastolic LV volume (r = -0.452; P < 0.001). In addition, the plasma proBNP/BNP levels inversely correlated with the CORIN expression (r = -0.362; P < 0.005).Decreased myocardial CORIN expression and the corresponding higher levels of circulating unprocessed proBNP in DCMP may partly account for the relative BNP resistance observed in patients with LV dysfunction.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Cardiovascular Research Center Aalst, (Aalst, Belgium) Introduction Breast cancer patients receiving anthracyclines are particularly prone to develop cancer therapeutics-related cardiac dysfunction (CTRCD). Early detection of cardiotoxicity onset is required for optimal timing of cardio protection treatment. The latest guidelines consider a relative reduction of 15% in global longitudinal strain (GLS) from baseline as risk for cardiotoxicity. Nevertheless, the more recent Myocardial Work Index (MWI) offers a load-independent tool for detection of subclinical heart failure (HF). Data in cancer patients are still scarce. Purpose This study analyses the predictive value of MWI for cardiotoxicity diagnosis after 6 months chemotherapy. Methods The study population consists of breast cancer patients referred for chemotherapy with anthracyclines and taxanes. Patients with a history of HF previous to chemotherapy or depressed LV function at baseline were excluded. Echocardiography was performed before onset of the chemotherapy (baseline) and after 6 months follow-up. LVEF, GLS and MWI were assessed offline using EchoPAC software. The values at baseline and 6 months follow-up were pairwise compared to detect subclinical cardiac dysfunction. Mean LVEF, GLS and MWI at baseline were taken as cut-off value to compare the predictive value of each parameter. Moreover, patients were categorized in one group with GLS reduction >15% (Group 1) and one group with GLS reduction Results From April 2016 to January 2020, 24 women with breast cancer were included (age 54 ± 11 years, LVEF 58 ± 4%, GLS -21 ± 2%, MWI 2181 ± 325 mmHg). All patients underwent the same standard chemotherapy protocol (4xEC, 12xTaxol). No difference in baseline characteristics between group 1 (n = 9) and group 2 (n = 15) was observed. At 6 months follow up a significant decrease in LVEF (53 ± 8%, p = 0.003), GLS (-19 ± 3%, p = 0.002) and MWI (1933 ± 410 mmHg, p = 0.005) was shown without any change in blood systolic pressure. However, while mean LVEF and GLS at baseline did not predict any significant change, patients with MWI under the mean value at baseline (n = 13) presented significant lower LVEF (49 ± 8%, p = 0.006), GLS (-18 ± 4%, p = 0.045), MWI (1753 ± 341 mmHg, p = 0.018) after 6 months. Additionally, both groups had similar MWI at baseline (2199 ± 390 mmHg vs 2170 ± 294 mmHg, p = 0.85), whereas those patients with GLS reduction >15% showed significant lower MWI after 6 months (1626 ± 344 mmHg vs 2116 ± 334 mmHg, p = 0.003, Figure 1). Conclusions At 6 months follow up, a decline of the LV systolic function as side effect of chemotherapy can be seen. In comparison to LVEF and GLS, MWI shows the best predictive value for development of early cardiotoxicity. Further studies are warranted to better understand the role of MWI in predicting CTRCD and its clinical relevance. Abstract Figure. Change in MWI

Introduction: The Sodium Glucose cotransporter (SGLT) and glucose transporters(GLUTs) play a crucial role in cellular glucose transport. Although experimental data have shown differential regulation of GLUT4 and SGLT in diabetic cardiomyopathy, the impact of diabetes mellitus (DM) upon myocardial glucose transporters in humans remains undetermined. Aim: To better understand the impact of elevated glucose levels upon myocardial expression of glucose transporters, the endomyocardial gene expression of GLUT1, GLUT4 and SGLT1 was investigated in heart transplant(HTx) recipients, with and without DM, who received a heart from a DM- donor. Methods: At baseline(BL), immediately after HTx and 12 ± 2 months(FU) later, serial endomyocardial biopsies were procured in 26 Htx pts, free of clinical or histological rejection, at time of routine surveillance biopsy. Patients were categorized in DM+ (n = 13pts) and DM- (n = 13 pts), according to the presence of diabetes mellitus (DM) at FU. Results: Despite similar hemodynamics and HbA1c levels at BL, DM+ pts had higher HbA1c levels (46,00 ± 13,79 vs 38,33 ± 4,88; p < 0,05) at FU. No differences were noted in BL GLUT1, GLUT4 and SGLT gene expression between both groups. In DM- pts SGLT1(0,081 ± 0,080 vs 0,188 ± 0,108; p = 0,0036) , GLUT4(0,076 ± 0,068 vs 0,137 ± 0,065; p = 0,0011 )and GLUT1(0,020 ± 0,021 vs 0,022 ± 0,009; p = 0,043) increased significantly at FU whereas no change was observed in DM+ pts. Conclusion: Similar to experimental data, differential endomyocardial regulation in SGLT1 and GLUT4 was noted between DM+ and DM-pts with a blunted upregulation of glucose transporters at 1 year in DM+ HTx pts. These observations are in line with experimental data and suggest that myocardial glucose uptake is differentially regulated in DM+ HTx pts.

A 53-year-old heart transplant recipient with a past medical history of surgically treated acute type A dissection of the donor aorta 10 years following heart transplantation, presented with a Card...

Purpose A pulmonary wedge pressure >18 mmHg following volume load has been proposed as a partition value for the detection of HFpEF. In both experimental and clinical settings, the hemodynamic changes in filling pressures have been attributed to a nitric oxide(NO)-mediated rightward shift of the pressure-volume relationship. The present study investigates the hemodynamic response to a volume challenge upon diastolic function in heart transplant(HTx) recipients and examines the role of inducible nitric oxide synthase(iNOS) gene expression on diastolic function changes. Methods 36 HTx recipients with normal left ventricular function (ejection fraction[EF]: 61 ± 12%) and without rejection and graft vasculopathy underwent right heart catheterization for the measurement of the degree of hemodynamic response to volume loading after saline infusion of 7 mL/kg over 10 min. Pulmonary capillary wedge pressure(PCWP), right atrial pressure(RAP), and mean pulmonary artery pressure(PA) were measured, following which the PCWP and stroke volume index(SVI) were used for Starling(SVI/PCWP) curve construction. Pts were categorized into the normal (group A, n=20) and abnormal hemodynamics (group B, n=16, PCWP >15 mmHg at rest or >18 mmHg following volume load) groups. For the establishment of the potential role of NO as a mediator of hemodynamic response, the iNOS endomyocardial gene expression level was measured . Results No differences were observed in terms of donor and recipient age, baseline hemodynamic parameters, and EF between both groups. Volume load significantly increased PCWP and PA in both groups, without any significant change in blood pressure or heart rate. Saline infusion was associated with a significant increase in SVI in group A but not group B. Moreover, in group A, the Starling curves revealed a higher SVI at any given PCWP. Group A exhibited significantly higher iNOS gene expression levels than Group B. Conclusion In HTx, rapid saline infusion increases the filling pressure and unmasks the presence of left ventricular diastolic dysfunction. Interestingly, pts with an abnormal hemodynamic response show a blunted Frank-Starling response, as evidenced by the higher PCWP and lack of SVi increase at any given PCWP. The higher iNOS gene expression level in our control group suggests the potential role of NO as a mediator of diastolic function in heart Tx patients.

Background. Cardiac allograft vasculopathy (CAV) remains the Achilles’ heel of long-term survival after heart transplantation (HTx). The severity and extent of CAV is graded with conventional coronary angiography (COR) which has several limitations. Recently, vessel“It is very important for the corresponding author to have a linked ORCID (Open Researcher and Contributor ID) account on MTS. To register a linked ORCID account, please go to the Account Update page (http://mts.hindawi.com/update/) in our Manuscript Tracking System and after you have logged in click on the ORCID link at the top of the page. This link will take you to the ORCID website where you will be able to create an account for yourself. Once you have done so, your new ORCID will be saved in our Manuscript Tracking System automatically.”"?> fractional flow reserve (vFFR) derived from COR has emerged as a diagnostic computational tool to quantify the functional severity of coronary artery disease. Purpose. The present study assessed the usefulness of vFFR to detect CAV in HTx recipients. Methods. In HTx patients referred for annual check-up, undergoing surveillance COR, the extent of CAV was graded according to the criteria proposed by the international society of heart and lung transplantation (ISHLT). In addition, three-dimensional coronary geometries were constructed from COR to calculate pressure losses using vFFR. Results. In 65 HTx patients with a mean age of 53.7 ± 10.1 years, 8.5 years (IQR 1.90, 15.2) years after HTx, a total number of 173 vessels (59 LAD, 61 LCX, and 53 RCA) were analyzed. The mean vFFR was 0.84 ± 0.15 and median was 0.88 (IQR 0.79, 0.94). A vFFR ≤ 0.80 was present in 24 patients (48 vessels). HTx patients with a history of ischemic cardiomyopathy (ICMP) had numerically lower vFFR as compared to those with non-ICMP (0.70 ± 0.22 vs. 0.79 ± 0.13, p=0.06). The use of vFFR reclassified 31.9% of patients compared to the anatomical ISHLT criteria. Despite a CAV score of 0, a pathological vFFR ≤ 0.80 was detected in 8 patients (34.8%). Conclusion. The impairment in epicardial conductance assessed by vFFR in a subgroup of patients without CAV according to standard ISHLT criteria suggests the presence of a diffuse vasculopathy undetectable by conventional angiography. Therefore, we speculate that vFFR may be useful in risk stratification after HTx.

Supplemental Digital Content is available in the text., Background. Endothelium-enriched microRNAs (miRs) are involved in the development of cardiac allograft vasculopathy (CAV). Recently, serum-derived miR-126-3p and -5p, known endothelial microRNAs with a crucial function in angiogenesis and re-endothelialization, provided additional predictive power for cardiac allograft vasculopathy in addition to clinical predictors. However, their myocardial expression in and relationship with CAV are still unknown. Our study aim was to investigate the expression of endomyocardial microRNA-126-3p and microRNA-126-5p levels in heart transplant recipients and their relationship with allograft vasculopathy. Methods. We studied 39 heart transplant recipients, 21 with proven allograft vasculopathy (CAV+) and 18 without allograft vasculopathy (CAV−) with serial coronary angiograms. Additionally, 8 patients with end-stage native coronary artery disease (CAD) were added to the study to investigate disease specificity of the microRNA signature. The mRNA levels of miR-126-3p and miR-126-5p were determined by qRT-PCR in the right ventricular endomyocardial biopsies obtained at baseline and during routine follow-up. Results. MiR-126-3p levels were significantly lower in the CAV+ group compared to the CAV− group at follow-up, while miR-126-5p levels were unaltered. This was in stark contrast to native CAD patients in whom miR-126-3p and -5p levels were significantly higher. qPCR levels of miR-126 targets are differentially regulated in CAV versus ischemic cardiomyopathy and are influenced by the administration of immunosuppressive agents in endothelial cells. Conclusions. Our data provide evidence for a distinct microRNA signature in heart transplantation patients with allograft vasculopathy. In contrast to CAD patients, lower miR-126-3p levels coincide with the development of cardiac allograft vasculopathy. Further studies in a larger patient population are warranted to determine if the serial measurement of myocardial microRNA-126 products could help in risk assessment and early detection of CAV.

Introduction A pulmonary capillary wedge pressure (PCWP) ≥25 mm Hg following volume load or exercise has been proposed as a partition value for detection of HfpEF. However, the hemodynamic response to volume challenge in heart transplant (Tx) recipients has never been studied. Methods 24 heart Tx recipients (age: 65 years) with normal LV function (55±7%) and without rejection and graft vasculopathy underwent right heart catheterization to measure hemodynamic response to volume loading before and after a rapid saline infusion of 7mL/kg over 10 min. PCWP, right atrial pressure (RAP), mean pulmonary artery pressure (AP) were obtained and the PCWP and indexed (i) stroke volume (SV) data were used to construct Starling (SVindex/PCWP) curves. Pts were categorized in those with elevated filling pressures (Group A, n=13 pts) defined by a PCWP ≥15 mm Hg at rest or ≥25 mm Hg following volume loading vs those without (Group B, n=11 pts). Results No difference in age of donor and transplant heart, baseline hemodynamics and EF was noted between both groups. Saline infusion significantly increased PCWP and mean AP in both Groups (table 1) without any significant change in BP and heart rate. Interestingly saline infusion was associated with a significant rise in SV and SVi in Group B not in Group A pts. Moreover, in Group B pts the Starling curves revealed a larger SVi at any give PCWP compared to Group A pts (Fig.1). Table 1 All (n=24) Group A (n=13) Group B (n=11) Baseline Volume Loading Baseline Volume Loading Baseline Volume Loading RAP (mm Hg) 5.3±4.1 9.2±4.8* 7.6±4.8 11.4±5.2* 3.8±2.5 7.3±1.9* Mean AP 18.4±5.4 24.1±5.9* 21.7±5.1 26.8±6.5** 14.9±2.4 20.8±2.6* PCWP 12.1±4.9 16.8±6.7* 15.0±4.9 19.8±6.5** 8.4±1.9 14.6±3.7* SV 71.4±19.6 72.5±23.6 73.2±6.2 72.4±6.2 69.2±14.6 79.2±3.9 SViml/m2) 37.4±9.2 37.9±11.2 36.7±7.1 38.7±9.9 35.3±6.0 40.5±5.2* *p Figure 1 Conclusions In the transplanted heart volume loading increases filling pressures and is able to unmask left ventricular diastolic dysfunction. Interestingly, those with HFpEF are characterized by a blunted Frank Starling response as evidenced by higher PCWP and failure to increase SV for any given PCWP. Further prospective studies are warranted to unravel the underlying mechanisms.

Post-extrasystolic potentiation (PESP) is a marker of contractile reserve and refers to the augmentation of left ventricular contractility due to preload recruitment and rise in intracellular calcium following a premature beat. In this case report we show that PESP might be a safe and helpful aid to evaluate low flow, low gradient aortic stenosis and contractile reserve in the cathlab, thereby reducing the potential risk of complications associated with intravenous dobutamine evaluation and reducing unnecessary testing.

Background The effect of adherence to cardiac rehabilitation (CR) on outcome is not clear. Therefore, we aimed to assess the impact of drop-out for non-medical reasons of CR on event-free survival in coronary artery disease (CAD). Methods A total of 876 patients who attended CR after acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) were included. Drop-out was defined as attending ≤50% of the training sessions. A combined endpoint of all-cause mortality and rehospitalization for a cardiovascular event was used to specify event-free survival. Differences in clinical characteristics were assessed and parameters with p Results A total of 15% died or had a cardiovascular event during a median follow-up period of 33 months (interquartile range 24, 51). Overall, 17% dropped out before finishing half of the program. Patients who withdrew prematurely had a risk twice as high for a cardiovascular event or death (hazard ratio 1.92, 95% confidence interval 1.28–2.90) than those who attended more than half of the sessions. Both ACS (2.36, 1.47–3.58) and PCI (2.20, 1.22–3.96), as primary indicators for CR, were associated with an adverse outcome and also a prior history of chronic heart failure (CHF) remained negatively associated with event-free survival (3.67, 1.24–10.91). Finally, the presence of hyperlipidemia was independently related to a worse outcome (1.48, 1.02–2.16). Conclusions Drop-out for non-medical reasons was independently associated with a negative outcome in CAD. Therefore, underlying factors for drop-out should gain more attention in future research and should be taken into account when organizing CR.

Background: Despite the clear benefits of cardiac rehabilitation (CR), a considerable number of patients drop out early. Objective: Therefore, we wanted to evaluate dropout in CR with a special focus on comorbidities and psychosocial background. Methods: Patients who attended CR after acute coronary syndrome, cardiac surgery, or heart failure (N = 489) were prospectively included. Dropout was defined as attending 50% of the training sessions or less (n = 96 [20%]). Demographic and clinical characteristics, exercise parameters, and psychosocial factors were analyzed according to dropout, and those with a trend toward a significant difference (P G .10) were entered in a multivariate logistic model. Results: The presence of a cerebrovascular accident (4.18 [1.39Y12.52]) involved a higher risk of dropout, and a comparable trend was seen for the presence of chronic obstructive pulmonary disease (2.55 [0.99Y6.54]). Attending the training program only twice per week also implicated a higher risk of an early withdrawal (3.76 [2.23Y6.35]). In contrast, patients on "-blockers were less likely to withdraw prematurely (0.47 [0.22Y0.98]). Singles were more likely to drop out (2.89 [1.56Y5.35]), as well as those patients who were dependent on others to get to CR (2.01 [1.16Y3.47]). Finally, the reporting of severe problems on the anxiety/depression subscale of the EuroQOL-5D questionnaire involved a higher odds for dropout (7.17 [1.46Y35.29]). Conclusions: Neither demographic characteristics nor clinical status or exercise capacity could independently identify patients who were at risk of dropout. The presence of comorbidities and a vulnerable psychosocial background rather seem to play a key role in dropout.

Purpose A mean pulmonary wedge pressure (mPAP) ≥ 25 mm Hg following volume load or exercise has been proposed as a partition value for detection of HfpEF. However, the hemodynamic response to volume challenge in heart transplant (Tx) recipients has never been studied. Methods 36 heart Tx recipients (Age: 65 years) with normal LV function (EF: 55 ± 7 %) and without rejection and graft vasculopathy underwent right heart catheterization to measure hemodynamic response to volume loading before and after a rapid saline infusion of 7mL/kg over 10 min. PCWP, right atrial pressure (RAP), mean pulmonary artery pressure(PA) were obtained and the PCWP and indexed(i) stroke volume(SV) data were used to construct Starling (SVindex/PCWP) curves. Pts were categorized in those with elevated filling pressures (Group DD, n=10 pts) defined by a PCWP ≥ 15 mm Hg at rest or ≥ 25 mm Hg following volume loading vs those without (Controls, n=26 pts). Results No difference in age of donor and transplant, baseline hemodynamics and EF was noted between both groups. Saline infusion significantly increased PCWP and mean PA in both Groups without any significant change in BP and heart rate. Interestingly saline infusion was associated with a significant rise in SV and SVi in Controls not in DD pts(Fig 1). Moreover, in DD pts the Starling curves revealed a larger SVi at any give PCWP compared to Controls pts. Conclusion In the transplanted heart volume loading increases filling pressures and is able to unmask left ventricular diastolic dysfunction. Interestingly, those with DD are characterized by a blunted Frank Starling response as evidenced by higher PCWP and failure to increase SV for any given PCWP. Further prospective studies are warranted to unravel the underlying mechanisms.

PURPOSE: Cardiac graft vasculopathy (CAV) remains the Achilles' heel of long-term survival after heart transplantation (HTx). The severity and extent of CAV is graded with conventional coronary angiography(COR) which has several limitations. Recently virtual fractional flow reserve (vFFR) derived from COR has emerged as a new diagnostic computational tool to functionally evaluate the extent of coronary artery disease. The present study assessed the usefulness of vFFR to detect CAV in HTx recipients. METHODS: In HTx pts referred for annual check-up, undergoing surveillance COR and normal LV systolic function, the extent of CAV was graded according to the ISHLT guidelines. Three-dimensional coronary geometries were constructed offline and generic boundary conditions for computational fluid dynamics analysis were applied to calculate vFFR. RESULTS: In 49 HTx pts with a mean age of 53.3 ± 11.0 years, 8.6 ± 7.1 years post HTx, a total number of 171 vessels(59 LAD, 60 Cx, 52 RCA) were analyzed. Mean vFFR in all HTx pts was 0.85 ± 0.15, median 0.89 [IQR 0.80, 0.95]. HTx pts with previous history of ischemic cardiomyopathy(ICMP) had significantly lower vFFR as compared to those with non-ICMP. Use of vFFR reclassified 33% of patients compared to the anatomical ISHLT criteria. A vFFR ≤ 0.80 was present in 24 pts (42 vessels). Despite a CAV score of 0, a pathological vFFR ≤ 0.80 was detected in 6 pts (25.0 %). Finally, pts with a vFFR ≤ 0.80 had significantly higher need for revascularization (Figure 1) vs those with normal vFFR (HR 9.18, 95% CI 1.18 to 71.2, p=0.03). CONCLUSION: The impairment of coronary flow assessed by vFFR in a subgroup of pts without CAV according to standard ISHLT criteria, suggests the presence of a diffuse vasculopathy undetectable by conventional COR. Similar to coronary atherosclerosis, a pathological vFFR bears prognostic information as evidenced by a higher need for revascularization when vFFR is low. Therefore, we speculate that vFFR may be a helpfull tool in risk stratification post HTx.

Diuretic resistance in acute heart failure is a common clinical problem, and it is associated with adverse outcomes. Effective therapies are still lacking. The Doraya catheter, a temporary intravenous flow regulator placed in the inferior vena cava below the level of the renal veins, is a novel device designed to target renal and cardiac congestion, thereby improving diuretic response. A first-in-man clinical study is currently ongoing.

Cardiac graft vasculopathy (CAV) remains the Achilles’ heel of long-term survival after heart transplantation (HTx). The severity of CAV is graded with coronary angiogram (COR) which has several known limitations. Vessel fractional flow reserve (vFFR) derived from COR has emerged as a new

The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in “third place,” i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper.

Whereas in the past ‘free’ and ‘illegal’ were nearly synonymous in the music industry, consumers nowadays face a myriad of music platforms with widely different characteristics in terms of business model (advertising supported, fee based, etc.), delivery mode (streaming, downloading, etc.), and others. The current research examines music consumption preferences in this new context. In order to break with the outmoded free-illegal versus paid-legal dichotomy, the present research studies consumer preferences for a broader range of music platform attributes, including free versus paying business models, (il)legality of use, artist revenues, downloading versus streaming, and audio quality. Based on a literature review and a qualitative study with in-depth interviews (N = 92), an online conjoint survey (N = 764) quantifies online music preferences. Results show that consumers of all ages clearly and consistently prefer legal and ethical options if available, but favor different ways of making this economically viable. Youngsters and young adults are more open to advertising, while middle-aged adults are more often willing to pay for advertising-free platforms. Thus, in real-life choices, youngsters may appear to be less ethical and law abiding, but the driving force behind this is mainly economical. Finally, a market segmentation provides deeper insights into online music consumer preferences and leads to recommendations on how to define viable legal and ethical music offerings.

Background— Hemodynamic monitoring using implantable devices may provide early warning of volume overload in patients with heart failure (HF). This study was designed to prospectively compare information from intrathoracic impedance monitoring and continuous right ventricular pressure measurements in patients with HF. Methods and Results— Sixteen patients with HF (age, 63.5±13.8 years; left ventricular ejection fraction, 23.2±11.3%; New York Heart Association, II and III) and a previous HF decompensation received both a cardiac resynchronization therapy defibrillator providing a daily average of intrathoracic impedance and an implantable hemodynamic monitor providing an estimate of the pulmonary artery diastolic pressure. At the end of a 6-month investigator-blinded period, baseline reference hemodynamic values were determined over 4 weeks during which the patient was clinically stable. A major HF event was defined as HF decompensation requiring hospitalization, IV diuretic treatment, or leading to death. Sixteen major HF events occurred in 10 patients. Within 30 days and 14 days before a major HF event, impedance decreased by 0.12±0.21 Ω/d and 0.20±0.20 Ω/d, respectively, whereas estimated pulmonary arterial diastolic pressure increased by 0.10±0.20 mm Hg/d and 0.16±0.15 mm Hg/d, respectively. During these periods, impedance decreased by 3.8±5.4 Ω ( P P P P r =−0.48±0.25). Within 30 days preceding a major HF event, this correlation improved to r =−0.58±0.24. Conclusions— Decompensated HF develops based on hemodynamic derangements and is preceded by significant changes in intrathoracic impedance and right ventricular pressures during the month prior to a major clinical event. Impedance and pressure changes are moderately correlated. Future research may establish the complementary contribution of both parameters to guide diagnosis and management of patients with HF by implantable devices.

ObjectivesThis study was designed to investigate: 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; and the 3) expression of ST2, membrane-anchored ST2L, and its ligand, interleukin (IL)-33, in myocardium, endothelium, and leukocytes from patients with left ventricular (LV) pressure overload and congestive cardiomyopathy.BackgroundSerum levels of ST2 are elevated in heart failure. The relationship of ST2 to hemodynamic variables, source of ST2, and expression of ST2L and IL-33 in the cardiovascular system are unknown.MethodsSerum ST2 (pg/ml; median [25th, 75th percentile]) was measured in patients with LV hypertrophy (aortic stenosis) (n = 45), congestive cardiomyopathy (n = 53), and controls (n = 23). ST2 was correlated to N-terminal pro-brain natriuretic peptide, C-reactive protein, and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. The levels of ST2, ST2L, and IL-33 were measured (reverse transcriptase-polymerase chain reaction) in myocardial biopsies and leukocytes. The ST2 protein production was evaluated in human endothelial cells. The IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium.ResultsThe ST2 protein was elevated in aortic stenosis (103 [65, 165] pg/ml, p < 0.05) and congestive cardiomyopathy (194 [69, 551] pg/ml, p < 0.01) versus controls (49 [4, 89] pg/ml) and correlated with B-type natriuretic peptide (r = 0.5, p < 0.05), C-reactive protein (r = 0.6, p < 0.01), and LV end-diastolic pressure (r = 0.38, p < 0.03). The LV ST2 messenger ribonucleic acid was similar in aortic stenosis and congestive cardiomyopathy versus control (p = NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. The IL-33 protein was expressed in coronary artery endothelium. Leukocyte ST2L and IL-33 levels were highly correlated (r = 0.97, p < 0.001).ConclusionsIn human hypertrophy and failure, serum ST2 correlates with the diastolic load. Though the heart, endothelium, and leukocytes express components of ST2/ST2L/IL-33 pathway, the source of circulating serum ST2 is extra-myocardial.

Congestive heart failure (CHF) is associated with a blunted force-frequency relation (FFR) and myocardial contractile reserve (MCR) partially from a downregulation of beta1-adrenoreceptors (beta1-AR). We investigated whether acute and chronic cardiac resynchronization therapy (CRT) was capable of reversing the blunted FFR and MCR and if this was associated with upregulation of beta1-AR.Left ventricle dP/dtmax was invasively measured in 10 CHF patients (New York Heart Association classor =3; ejection fraction25%) during incremental dual chamber (DDD)-CRT pacing at 70, 90, 110, and 130 beats/min, with and without continuous infusion of intravenous dobutamine, immediately after CRT implantation (BL) and 4 months later (FU). In a subgroup of 5 patients, serial left ventricle beta1 and beta2-AR gene expression was measured using reverse transcriptase-polymerase chain reaction. Four months after the initiation of resynchronization therapy, DDD-CRT pacing results in a significant upward shift of the heart rate versus LV dP/dtmax relationship (P.01) with force frequency amplification as evidenced by the steeper slope of the force frequency response (P = .04). Infusion of dobutamine recruits myocardial contractile reserve and increases the heart rate versus LV dP/dtmax relationship at BL and at FU (both P.05). However, only at follow-up was an additional force frequency amplification noticed (P.05) during dobutamine infusion. This observation was paralleled by a significant upregulation of beta1-AR gene expression (P = .02).Chronic CRT is associated with a partial restoration of the FFR and with a recruitment in myocardial contractile reserve, which is paralleled by upregulation of beta1-AR.

Pulsed-wave tissue Doppler imaging (TDI) was shown to predict short-term left ventricular functional recovery after cardiac resynchronization therapy (CRT). However, few data are available regarding the baseline cardiac asynchrony and clinical outcome after CRT. Therefore, we aimed to investigate the prognostic value of pre-CRT cardiac asynchrony on clinical outcome after CRT.The study population consisted of 48 consecutive patients with moderate to severe heart failure and a wide QRS complex undergoing implantation of biventricular pacemaker. Cardiac asynchrony was assessed at pulsed-wave TDI from measurements of regional electromechanical coupling times in basal segments of both ventricles (Sum asynchrony). Clinical end-points were cardiac mortality and hospitalization for worsening heart failure.During a follow-up period of 970+/-319 days, clinical end-point (9 deaths, 15 hospitalizations) occurred in 24 patients (clinical nonresponders). At baseline, responders showed higher asynchrony than nonresponders (153+/-57 ms vs. 103+/-58 ms, p0.01). Sum asynchrony of98 ms showed the highest accuracy (AUC=0.80, sensitivity 92%, specificity 67%) to identify responders. In contrast, baseline NYHA class, conventional echo-Doppler indices and QRS complex duration were similar in both groups. Eight end-point events (3 deaths) occurred in 30 patients with significant Sum asynchrony (98 ms) as compared to 16 events (6 deaths) in 18 patients with smaller Sum asynchrony (27% vs. 89%; HR 0.14; 95% CI 0.04 to 0.46; p0.001). Favorable clinical outcome was associated with larger left ventricular functional recovery at 2 years follow-up (p0.001).TDI-derived index of baseline intra- and interventricular asynchrony appears to predict long-term clinical outcome after CRT.

Objectives We studied whether functional improvement after cardiac resynchronization therapy (CRT) is associated with reversal of the heart failure (HF) gene program. Background Cardiac resynchronization therapy improves exercise tolerance and survival in patients with advanced congestive HF and dyssynchrony. Methods Twenty-four patients referred for CRT underwent left ventricular (LV) endomyocardial biopsies immediately before CRT implantation (baseline). In addition, 17 of them underwent LV endomyocardial biopsy procurement 4 months later (follow-up). In 6 control patients with normal LV function, LV biopsies were obtained at the time of coronary artery bypass grafting. The LV messenger ribonucleic acid (mRNA) levels of contractile and calcium regulatory genes were measured by quantitative real time polymerase chain reaction and normalized for glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The HF patients showing an improvement in New York Heart Association (NYHA) functional class by >1 score and a relative increase in LV ejection fraction ≥25% at 4 months after CRT were considered as responders. Results The HF patients were characterized by lower LV mRNA levels of α-myosin heavy chain (α-MHC), β-myosin heavy chain (β-MHC), sarcoplasmic reticulum calcium ATPase 2α (SERCA), phospholamban (PLN), and higher brain natriuretic peptide (BNP) mRNA levels as compared with control subjects. Responders to CRT (n = 11) showed an increase in LVEF (p Conclusions In HF patients with electromechanical cardiac dyssynchrony, functional improvement related to CRT is associated with favorable changes in established molecular markers of HF, including genes that regulate contractile function and pathologic hypertrophy.

Heart failure is associated with a reduction in left ventricular (LV) contractility as evidenced by a blunted force-frequency response (FFR) and downregulation of contractility regulating genes.This study sought to investigate whether cardiac resynchronization therapy (CRT) is capable of reversing the blunted FFR and the downregulation of contractility regulating genes.Twenty heart failure patients underwent echocardiographic examination during incremental AAI and DDD-CRT pacing at 70, 90, and 110 beats/min, immediately after and 4 months after CRT implantation. The FFR was determined from the ratio of the LV systolic pressure/end systolic volume index at given heart rate. In a subgroup of 6 patients with idiopathic dilated cardiomyopathy, serial LV dP/dtmax was invasively measured during both pacing modes and serial LV endomyocardial biopsies were taken to measure sarcoplasmatic reticulum calcium ATPase 2alpha (SERCA2alpha), phospholamban (PLN), sarcolemmal sodium calcium exchanger (NCX), beta1-adrenoreceptor (beta1-AR), and apelin (APL) gene expression using reverse-transcriptase polymerase chain reaction.Acutely, DDD-CRT pacing was associated with a decrease in dyssynchrony (P.01) and increase in diastolic filling time (P.01) at all heart rates paralleled by an upward shift of the FFR (P.01) without force-frequency amplification. A greater upward shift of the FFR was noticed during DDD-CRT as compared with AAI (P.01) after 4 months. In addition, CRT was associated with a significant force-frequency amplification at follow-up as evidenced from the steeper slope of the FFR relationship (P = .039). This was associated with a significant upregulation of SERCA2alpha P = .01), PLN (P = .01), their ratio (P = .01), ratio of SERCA/NCX (P = .02), beta1-AR (P = .03), and APL (P = .01) mRNA levels.CRT is associated with an acute upward shift in the FFR without force-frequency amplification related to restored synchronicity and increased filling time of the LV. Only chronic CRT is associated with force-frequency amplification in parallel to upregulation of contractility regulating genes.

Background Both endurance training (ET) and cardiac resynchronization therapy (CRT) improve quality of life (QOL) and exercise tolerance in patients with advanced chronic heart failure (CHF). Design A randomized intervention trial to study the effect on exercise capacity of ET in addition to CRT in patients with CHF and dyssynchrony. Methods Seventeen patients (eight men, aged 59 9 years) with CH F and dyssynchrony were randomized to CRT with (n = 8) or without (n = 9) ET and compared with two matched control CH F groups (standard care with ET: n = 9, standard care only: n = 10). At baseline and after 5 months, exercise tolerance, left ventricular (LV) remodelling, QOL and NT-pro brain natriuretic peptide (NT-proBNP) levels were assessed. Results Peak oxygen consumption (Vo(2)peak), maximal workload (Wattmax), circulatory power, LV ejection fraction, dyssynchrony and QOL improved in both CRT groups. However, the increase in Vo(2)peak (+ 40% versus + 16%, P = 0.005), Wattmax (+43% versus + 13%, P=0.0005), and circulatory power (+74% versus + 32%, P=0.01), was significantly greater in the trained versus the untrained CRT patients. Comparison of the four patient groups confirmed the cumulative effects of CRT plus ET. Conclusions ET in resynchronized CHF patients is feasible and further enhances exercise tolerance. Patients with severe CHF should be prescribed an exercise training programme after implantation in order to maximize the expected benefit.

Aims Exercise-induced mitral regurgitation (MR) bears a poor prognosis in patients with congestive heart failure (CHF). Cardiac resynchronization therapy (CRT) is associated with improved clinical outcome but its effects on exercise-induced MR remain undetermined. We investigated serial changes in functional MR in relation to left ventricular (LV) remodelling and cardiopulmonary performance after CRT. Methods and results Twenty-eight patients with CHF (LV ejection fraction 25 ± 7%), broad QRS complex (171 ± 27 ms), and at least mild MR [effective regurgitant orifice (ERO) 0.25 ± 0.12 cm2] were studied with quantitative exercise echocardiography and cardiopulmonary exercise testing prior, within 1 week, and 3 months after CRT. Early after CRT, a decrease in LV dyssynchrony (from 54 ± 21 to 19 ± 7 ms, P < 0.001) and in MR at rest (ERO from 0.25 ± 0.12 to 0.20 ± 0.10 cm2, P = 0.047) was observed. However, no change in exercise-induced increase in MR was observed (ERO from 0.34 ± 0.12 to 0.31 ± 0.16 cm2, NS). Three months after CRT, a decrease in the mitral valve tenting area (from 3.3 ± 1.2 to 2.0 ± 0.6 cm2, P < 0.001) and an increase in LV sphericity index (from 1.5 ± 0.3 to 1.8 ± 0.5, P < 0.001) were paralleled by an attenuation of exercise-induced MR (ERO 0.19 ± 0.06 cm2, P = 0.001 vs. prior CRT). This was associated with an increase in LV ejection fraction (from 25 ± 7 to 35 ± 9%, P < 0.001), peak oxygen uptake (from 11.7 ± 2.4 to 13.7 ± 3.8 mL/kg/min, P = 0.001), and a decrease in Nt-pro-BNP (from 2777 ± 1681 to 1963 ± 1361 pg/mL, P = 0.067). Conclusion CRT is associated with acute decrease in resting MR but does not immediately attenuate exercise-induced MR. In contrast, only late, CRT-induced reversed LV remodelling and reduced mitral apparatus deformation are associated with a reduction in both resting and exercise-induced MR and with an improvement in cardiopulmonary performance.

Background The aim of cardiac resynchronization therapy is correction of left ventricular (LV) dyssynchrony. However, little is known about the optimal timing of LV and right ventricular (RV) stimulation. Objectives The purpose of this study was to evaluate the acute hemodynamic effects of biventricular pacing, using a range of interventricular delays in patients with advanced heart failure. Methods Twenty patients with dilated ischemic (n = 12) and idiopathic (n = 8) cardiomyopathy (age 66 ± 6 years, New York Heart Association class III–IV, LV end-diastolic diameter >55 mm, ejection fraction 22% ± 18%, and QRS 200 ± 32 ms) were implanted with a biventricular resynchronization device with sequential RV and LV timing (VV) capabilities. Tissue Doppler echocardiographic parameters were measured during sinus rhythm before implantation and following an optimal AV interval with both simultaneous and sequential biventricular pacing. The interventricular interval was modified by advancing the LV stimulus (LV first) or RV stimulus (RV first) up to 60 ms. For each stimulation protocol, standard echocardiographic Doppler and tissue Doppler imaging (TDI) echo were used to measure the LV outflow tract velocity-time integral, LV filling time, intraventricular delay, and interventricular delay. Results The highest velocity-time integral was found in 12 patients with LV first stimulation, 5 patients with RV first stimulation, and 3 patients with simultaneous biventricular activation. Compared with simultaneous biventricular pacing, the optimized sequential biventricular pacing significantly increased the velocity-time integral ( P P = .001) and decreased interventricular delay ( P = .013) and intraventricular delay ( P = .010). The optimal VV interval could not be predicted by any clinical nor echocardiographic parameter. At 6-month follow-up, the incidence of nonresponders was 10%. Conclusion Optimal timing of the interventricular interval results in prolongation of the LV filling time, reduction of interventricular asynchrony, and an increase in stroke volume. In patients with advanced heart failure undergoing cardiac resynchronization therapy, LV hemodynamics may be further improved by optimizing LV–RV delay.

Background Long-term survivors of heart transplantation are often confronted with chronic kidney disease, by definition related to the intake of calcineurin-inhibitors. Sirolimus is increasingly proposed as an alternative immunosuppressive agent due to its absence of nephrotoxicity. Methods Between November 2002 and November 2003, 9 adult heart transplant candidates with moderate to severe chronic renal disease were switched from cyclosporine to sirolimus. The conversion scheme consisted of an immediate stop of cyclosporine and an 8-mg loading dose of sirolimus, followed by 3 mg/d; after 1 week, the sirolimus dose was adjusted to maintain trough levels between 5 and 15 μg/L. The majority of patients were on corticosteroids, and on either azathioprine or mycophenolate mofetil. At conversion, the mean serum creatinine level was 2.11 (±0.4) mg/dL and the mean glomerular filtration rate (GFR) was 32 (±7) mL/min/1.73 m 2 . Prior to conversion, the renal dysfunction was predominantly stable. Results After conversion, there were 7 dropouts (75%) due to several side effects related to sirolimus: edema (n = 2), general discomfort (n = 2), delayed wound healing (n = 1), cardiac thrombus (n = 1), and diarrhea (n = 1). The median treatment time with Sirolimus, therefore, was only 4.0 months. While on sirolimus, the renal function of all patients remained unchanged or showed even some improvement. Retrospective nephrological review revealed severe renal artery stenoses in 2 patients and serious generalized abdominal and renal atheromatosis in 7 patients. No cardiac dysfunction was seen. Conclusion Conversion from cyclosporine to sirolimus was problematic due to sirolimus side effects, occurring at any time after the switch. One should also question whether chronic kidney disease after heart transplantation is routinely caused by the administration of calcineurin-inhibitors, in view of the generalized renal and abdominal atheromatosis.

ObjectivesWe postulated that both diastolic and systolic load modulate B-type natriuretic peptide (BNP) production in human pressure overload hypertrophy/failure.BackgroundIn isolated myocytes, diastolic stretch induces BNP messenger ribonucleic acid expression. However, the mechanism of the BNP release in human hypertrophy remains controversial.MethodsIn 40 patients with symptomatic aortic stenosis (AS), left ventricular (LV) performance and systolic and diastolic wall stress were calculated from combined invasive and echocardiographic data. Plasma BNP was determined by the rapid point-of-care bedside analyzer (Biosite Triage, Biosite Diagnostics Inc., San Diego, California).ResultsA significant relationship was observed between plasma BNP and pulmonary capillary wedge pressure (p < 0.001), fractional shortening (p = 0.001), and aortic valve area (p = 0.006). Furthermore, a significant correlation was noted between BNP and LV mass index (p = 0.005) as well as between BNP and markers of diastolic load such as LV end-diastolic wall stress (p = 0.011), indexed LV end-diastolic volume (p < 0.001), and isovolumic relaxation time (p = 0.02). Preoperative BNP levels were elevated in patients with AS compared with patients without AS. Plasma BNP was higher in AS patients with impaired versus normal preload reserve (297 ± 56 pg/ml vs. 168 ± 44 pg/ml; p = 0.017) and in AS patients with clinical deterioration after valve replacement compared with those without (399 ± 82 pg/ml vs. 124 ± 41 pg/ml; p = 0.011).ConclusionsIn patients with AS, BNP appears to be regulated not only by systolic but also by diastolic load. This supports the hypothesis that myocardial stretch modulates BNP production in human pressure overload hypertrophy/failure.