Background: Long-term effects of cardiac autologous cell therapy are not well known. We performed... more Background: Long-term effects of cardiac autologous cell therapy are not well known. We performed a 3 year follow-up of the ASTAMI study. Patients with acute ST-elevation anterior wall myocardial infarctions were initially randomized to either intracoronary injection of autologous mononuclear bone marrow cells (mBMCs) (n=50) or control (n=50). At 6 months, LV ejection fraction improved in both groups, with no significant difference between groups. Methods: All eligible patients underwent MRI with a 1,5 T scanner (Siemens) 2–3 weeks, 6 months and mean(SD) 3,2 (0,2) years after myocardial infarction and stem cell injection. Infarct size was determined from gadolinium late-enhancement MR images. All images were analyzed by experienced observers blinded for treatment assignment. Left ventricular volumes were calculated by the area-length method. Results: There was no significant difference in EDV, ESV or LVEF between baseline and 3 years in neither group. Infarction volume was reduced a...
Introduction: Elite endurance athletes often develop left ventricular dilatation comparable to th... more Introduction: Elite endurance athletes often develop left ventricular dilatation comparable to that observed in aortic regurgitation (AR). Hypothesis: We hypothesized that the LV remodeling observed in athlete’s heart differs from that seen in AR, and that the difference may be attributed to different fiber stress distribution. Methods: Thirty asymptomatic patients with moderate to severe AR, 15 age matched elite endurance athletes (Athl) and 17 age matched healthy controls (C) where analyzed with 3D speckle tracking echocardiography. We calculated the ratio between peak systolic circumferential (CS) - and peak systolic longitudinal strain (LS) and end-systolic (ES) circumferential (ESSc) and meridional (ESSm) fiber stress. Results: LV ejection fraction in C, Athl and AR patients was (61 ± 2, 61 ± 3 and 62 ± 3%, respectively, p=NS). LV end-diastolic volume was 78 ± 11, 112 ± 13 and 117 ± 20 ml/m 2 in C, Athl and AR, respectively, (C vs AR and Athl, p<0.01, AR vs Athl, p=NS). A no...
Introduction: Diastolic dysfunction in aortic regurgitation (AR) is present at an early stage of ... more Introduction: Diastolic dysfunction in aortic regurgitation (AR) is present at an early stage of the disease. Yet, the mechanisms are not clearly understood. Hypothesis: We hypothesized that diastolic dysfunction in AR patients is caused by increased longitudinal (meridional) fiber stress and subsequent impaired relaxation of the corresponding subendocardial (longitudinal) fibers. Methods: Thirty asymptomatic patients with moderate to severe aortic regurgitation (AR) and 17 age matched healthy controls (C) where analyzed (32 ± 7 and 35 ± 4 (SD) years, respectively, p=NS) with 3D speckle tracking echocardiography. We measured early diastolic longitudinal- (LSRe) and circumferential (CSRe) strain rate (1/s) as the time derivative of strain (%) and the peak difference (LSRe – CSRe) during isovolumic relaxation (IVR). Early diastolic flow rate (sec -1 ) was estimated as the time derivative of the LV volume curve normalized to end-diastolic volume (EDV). Finally, we calculated end-systol...
Current diagnosis of heart failure with preserved ejection fraction (HFpEF) is suboptimal. We tes... more Current diagnosis of heart failure with preserved ejection fraction (HFpEF) is suboptimal. We tested the hypothesis that comprehensive machine learning (ML) of left ventricular function at rest and exercise objectively captures differences between HFpEF and healthy subjects. One hundred fifty-six subjects aged >60 years (72 HFpEF+33 healthy for the initial analyses; 24 hypertensive+27 breathless for independent evaluation) underwent stress echocardiography, in the MEDIA study (Metabolic Road to Diastolic Heart Failure). Left ventricular long-axis myocardial velocity patterns were analyzed using an unsupervised ML algorithm that orders subjects according to their similarity, allowing exploration of the main trends in velocity patterns. ML identified a continuum from health to disease, including a transition zone associated to an uncertain diagnosis. Clinical validation was performed (1) to characterize the main trends in the patterns for each zone, which corresponded to known char...
European heart journal cardiovascular Imaging, Jan 22, 2018
To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognost... more To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. 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 recomme...
Aortic valve replacement (AVR) improves survival and quality of life in patients with severe aort... more Aortic valve replacement (AVR) improves survival and quality of life in patients with severe aortic stenosis (AS), but despite clear indications for surgical treatment a significant proportion of patients do not undergo AVR. The study aim was to identify clinical variables associated with the decision to perform AVR, and to assess the prognostic effect of surgery versus medical treatment in patients with severe AS adjusted for significant confounders and effect modifiers. A prospective observational study of consenting patients aged >18 years who were under consideration for AVR at the authors' tertiary teaching hospital was conducted. The main outcomes of the study were treatment decisions and survival. Among 480 patients with severe AS who were evaluated, 351 had surgical AVR, 38 had transcatheter AVR, and 91 were declined operative treatment. Typically, non-operated patients were older, were in a lower NYHA class, had fewer symptoms, a lower peak aortic jet velocity, a hig...
European heart journal cardiovascular Imaging, Aug 19, 2017
The interaction between asynchronous regional myocardial activation and left ventricular (LV) wal... more The interaction between asynchronous regional myocardial activation and left ventricular (LV) wall remodelling has not been well established. We investigated the relationship between time of onset of longitudinal shortening (Tonset), regional myocardial work, and segmental LV wall thickness (SWT) in patients treated with cardiac resynchronization therapy (CRT). We analysed 26 patients with sinus rhythm, non-ischaemic cardiomyopathy (63 ± 9 years, 69% male, QRS duration 174 ± 18 ms) and positive response to CRT (15% reduction in end-systolic volume). Longitudinal strain was obtained by 2D speckle-tracking echocardiography before and after [14.5 (7-29) months] CRT. Tonset and SWT were measured in 18 segments per LV. Segmental myocardial work was calculated from non-invasive segmental stress-strain loop area. Before CRT, Tonset was the shortest in septal and anteroseptal and the longest in lateral and posterior walls (P < 0.001) and not different after CRT (P = 0.733). Before CRT, s...
The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM... more The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/ sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling.
Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis... more Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis, and inflammation. Blocking the Wnt ligand Wnt5a prevents HF in animal models. However, the role of Wnt5a in human HF and its functions in cardiac cells remain unclear. Here, we investigated Wnt5a regulation in HF patients and its effects on primary mouse and human cardiac fibroblasts. Serum Wnt5a was elevated in HF patients and associated with hemodynamic, neurohormonal, and clinical measures of disease severity. In failing human hearts, Wnt5a protein correlated with interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1. Wnt5a messenger RNA (mRNA) levels were markedly upregulated in failing myocardium and both mRNA and protein levels declined following left ventricular assist device therapy. In primary mouse and human cardiac fibroblasts, recombinant Wnt5a dose-dependently upregulated mRNA and protein release of IL-6 and TIMP-1. Wnt5a did not affect β-catenin levels, but activated extracellular signalregulated kinase 1/2 (ERK1/2) signaling. Importantly, inhibition of ERK1/2 activation attenuated Wnt5a-induced release of IL-6 and TIMP-1. In conclusion, our results show that Wnt5a is elevated in the serum and myocardium of HF patients and is associated with measures of progressive HF. Wnt5a induces IL-6 and TIMP-1 in cardiac fibroblasts, which might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.
European Heart Journal - Cardiovascular Imaging, 2017
Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may no... more 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.
Journal of Cardiovascular Translational Research, 2017
In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involvin... more In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and noncanonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in endstage DCM, possibly mediating different effects on cardiac function. Keywords Dilated cardiomyopathy. Diastolic dysfunction. Delta-like Notch ligand 1 (DLL1). Delta-like 1 homologue (DLK1). Periostin (POSN). Notch pathway. Myocardial remodeling Abbreviations DCM Dilated cardiomyopathy DLL1 Delta-like Notch ligand 1 DLK1 Delta-like 1 homologue POSN Periostin Associate Editor Daniel P. Judge oversaw the review of this article Electronic supplementary material The online version of this article
This investigation assessed the ability of a non-invasive method to reproduce aortic root pressur... more This investigation assessed the ability of a non-invasive method to reproduce aortic root pressure waveform and pressures. An external pulse tracing of the subclavian artery was obtained simultaneously with direct aortic root pressures during routine left heart catheterization in 26 patients (aged 39-74 years) with various cardiovascular disorders. Indirect brachial arterial peak-systolic and nadir-diastolic pressures were obtained with oscillometry. The direct and indirect peak-systolic and nadir-diastolic pressures, were separately used to calibrate the pulse tracing. Adequate pulse tracing was obtained in 19 patients (73%). The waveforms agreed well with cross-correlation coefficients for systole and diastole of 0.98. The difference between the pulse trace and the direct pressure curve, when the first was calibrated with the peak-systolic and nadir-diastolic pressures of the latter on average was less than 1 mmHg for systole and diastole. At end-systole the mean difference was 5 mmHg. Oscillometric brachial arterial peak-systolic pressures were (mean +/- SD) 3 +/- 7 mmHg below the corresponding direct measurements, while diastolic pressures were 8 +/- 4 mmHg above. The difference between the pulse trace and the direct pressure curve, when the pulse trace was calibrated with oscillometric pressures, was at end-systole 6 +/- 6 mmHg and for mean arterial pressures 5 +/- 4 mmHg. Thus, the external subclavian arterial pulse tracing provides a non-invasive, clinically feasible access to the aortic root pressure waveform. With optimal calibration, good estimates of aortic root pressures throughout systole and diastole can be obtained, while end-systolic pressure tends to be slightly overestimated.
Journal of the American College of Cardiology, 2017
Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is... more Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is usually guided by brachial cuff blood pressure (BP), but questions have been raised regarding accuracy. This comprehensive analysis determined the accuracy of cuff BP and the consequent effect on BP classification compared with intra-arterial BP reference standards. Three individual participant data meta-analyses were conducted among studies (from the 1950s to 2016) that measured intra-arterial aortic BP, intra-arterial brachial BP, and cuff BP. A total of 74 studies with 3,073 participants were included. Intra-arterial brachial systolic blood pressure (SBP) was higher than aortic values (8.0 mm Hg; 95% confidence interval [CI]: 5.9 to 10.1 mm Hg; p < 0.0001) and intra-arterial brachial diastolic BP was lower than aortic values (-1.0 mm Hg; 95% CI: -2.0 to -0.1 mm Hg; p = 0.038). Cuff BP underestimated intra-arterial brachial SBP (-5.7 mm Hg; 95% CI: -8.0 to -3.5 mm Hg; p < 0.0001...
Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in ac... more Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in acute coronary syndromes. We evaluated the effect of the IL-6 receptor antagonist tocilizumab on coronary microvascular function and endothelial dysfunction measured by coronary flow reserve (CFR) and markers of endothelial cell activation in patients with non-ST-elevation myocardial infarction (NSTEMI). This substudy was part of a two-centre, double-blind, randomised, placebo-controlled trial evaluating the effect of a single dose of tocilizumab in NSTEMI. Markers of endothelial cell activation (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 and von Willebrand factor) were assessed in 117 patients. In 42 of these patients, 20 assigned to placebo and 22 to tocilizumab, we measured CFR. Blood samples were obtained at seven consecutive time points between day 1 and 3. CFR was measured by transthoracic echocardiography during hospitalisation and after 6 months. To...
European heart journal cardiovascular Imaging, Jan 25, 2017
The European Association for Cardiovascular Imaging (EACVI) has outlined the rationale for settin... more The European Association for Cardiovascular Imaging (EACVI) has outlined the rationale for setting appropriate use criteria (AUC) in cardiovascular (CV) imaging. Transthoracic echocardiography (TTE) is the most common imaging modality in CV disease and is a central tool in diagnosis, follow-up, management planning and intervention. The purpose of AUC is to inform referrers, both to avoid under-use, which may result in incomplete or incorrect diagnosis and treatment, and also over-use, which may delay correct diagnosis, lead to 'treatment cascade', and wastes resources. The first step in defining AUC for TTE in the adult has been for a panel of experts in echocardiography to review the evidence, guidelines, recommendations, and position papers from the European Society of Cardiology, EACVI and other specialist societies, and current state-of-the-art clinical practice. The attached document summarizes this work, which will be used to under-pin the development of AUC.
Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, Jan 5, 2017
The role of speckle-tracking echocardiography in the assessment of chronic aortic regurgitation (... more The role of speckle-tracking echocardiography in the assessment of chronic aortic regurgitation (AR) is not established. Load dependency may encumber the interpretation of strain measurements in the chronically overloaded left ventricle. The aim of this study was to investigate the mechanisms of left ventricular (LV) contraction patterns in asymptomatic patients with moderate to severe AR and preserved ejection fractions. In this prospective, cross-sectional study, 31 patients with moderate to severe AR, 15 elite endurance athletes, and 17 healthy control subjects were examined using three-dimensional speckle-tracking echocardiography. Global circumferential strain (GCS), global longitudinal strain (GLS), end-systolic circumferential wall stress (ESSc), end-systolic meridional wall stress (ESSm), and the wall stress ratio (ESSc/ESSm) were measured. LV end-diastolic volumes were similar in athletes and patients with AR and significantly larger than in healthy control subjects. Values...
Background: Long-term effects of cardiac autologous cell therapy are not well known. We performed... more Background: Long-term effects of cardiac autologous cell therapy are not well known. We performed a 3 year follow-up of the ASTAMI study. Patients with acute ST-elevation anterior wall myocardial infarctions were initially randomized to either intracoronary injection of autologous mononuclear bone marrow cells (mBMCs) (n=50) or control (n=50). At 6 months, LV ejection fraction improved in both groups, with no significant difference between groups. Methods: All eligible patients underwent MRI with a 1,5 T scanner (Siemens) 2–3 weeks, 6 months and mean(SD) 3,2 (0,2) years after myocardial infarction and stem cell injection. Infarct size was determined from gadolinium late-enhancement MR images. All images were analyzed by experienced observers blinded for treatment assignment. Left ventricular volumes were calculated by the area-length method. Results: There was no significant difference in EDV, ESV or LVEF between baseline and 3 years in neither group. Infarction volume was reduced a...
Introduction: Elite endurance athletes often develop left ventricular dilatation comparable to th... more Introduction: Elite endurance athletes often develop left ventricular dilatation comparable to that observed in aortic regurgitation (AR). Hypothesis: We hypothesized that the LV remodeling observed in athlete’s heart differs from that seen in AR, and that the difference may be attributed to different fiber stress distribution. Methods: Thirty asymptomatic patients with moderate to severe AR, 15 age matched elite endurance athletes (Athl) and 17 age matched healthy controls (C) where analyzed with 3D speckle tracking echocardiography. We calculated the ratio between peak systolic circumferential (CS) - and peak systolic longitudinal strain (LS) and end-systolic (ES) circumferential (ESSc) and meridional (ESSm) fiber stress. Results: LV ejection fraction in C, Athl and AR patients was (61 ± 2, 61 ± 3 and 62 ± 3%, respectively, p=NS). LV end-diastolic volume was 78 ± 11, 112 ± 13 and 117 ± 20 ml/m 2 in C, Athl and AR, respectively, (C vs AR and Athl, p<0.01, AR vs Athl, p=NS). A no...
Introduction: Diastolic dysfunction in aortic regurgitation (AR) is present at an early stage of ... more Introduction: Diastolic dysfunction in aortic regurgitation (AR) is present at an early stage of the disease. Yet, the mechanisms are not clearly understood. Hypothesis: We hypothesized that diastolic dysfunction in AR patients is caused by increased longitudinal (meridional) fiber stress and subsequent impaired relaxation of the corresponding subendocardial (longitudinal) fibers. Methods: Thirty asymptomatic patients with moderate to severe aortic regurgitation (AR) and 17 age matched healthy controls (C) where analyzed (32 ± 7 and 35 ± 4 (SD) years, respectively, p=NS) with 3D speckle tracking echocardiography. We measured early diastolic longitudinal- (LSRe) and circumferential (CSRe) strain rate (1/s) as the time derivative of strain (%) and the peak difference (LSRe – CSRe) during isovolumic relaxation (IVR). Early diastolic flow rate (sec -1 ) was estimated as the time derivative of the LV volume curve normalized to end-diastolic volume (EDV). Finally, we calculated end-systol...
Current diagnosis of heart failure with preserved ejection fraction (HFpEF) is suboptimal. We tes... more Current diagnosis of heart failure with preserved ejection fraction (HFpEF) is suboptimal. We tested the hypothesis that comprehensive machine learning (ML) of left ventricular function at rest and exercise objectively captures differences between HFpEF and healthy subjects. One hundred fifty-six subjects aged >60 years (72 HFpEF+33 healthy for the initial analyses; 24 hypertensive+27 breathless for independent evaluation) underwent stress echocardiography, in the MEDIA study (Metabolic Road to Diastolic Heart Failure). Left ventricular long-axis myocardial velocity patterns were analyzed using an unsupervised ML algorithm that orders subjects according to their similarity, allowing exploration of the main trends in velocity patterns. ML identified a continuum from health to disease, including a transition zone associated to an uncertain diagnosis. Clinical validation was performed (1) to characterize the main trends in the patterns for each zone, which corresponded to known char...
European heart journal cardiovascular Imaging, Jan 22, 2018
To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognost... more To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. 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 recomme...
Aortic valve replacement (AVR) improves survival and quality of life in patients with severe aort... more Aortic valve replacement (AVR) improves survival and quality of life in patients with severe aortic stenosis (AS), but despite clear indications for surgical treatment a significant proportion of patients do not undergo AVR. The study aim was to identify clinical variables associated with the decision to perform AVR, and to assess the prognostic effect of surgery versus medical treatment in patients with severe AS adjusted for significant confounders and effect modifiers. A prospective observational study of consenting patients aged >18 years who were under consideration for AVR at the authors' tertiary teaching hospital was conducted. The main outcomes of the study were treatment decisions and survival. Among 480 patients with severe AS who were evaluated, 351 had surgical AVR, 38 had transcatheter AVR, and 91 were declined operative treatment. Typically, non-operated patients were older, were in a lower NYHA class, had fewer symptoms, a lower peak aortic jet velocity, a hig...
European heart journal cardiovascular Imaging, Aug 19, 2017
The interaction between asynchronous regional myocardial activation and left ventricular (LV) wal... more The interaction between asynchronous regional myocardial activation and left ventricular (LV) wall remodelling has not been well established. We investigated the relationship between time of onset of longitudinal shortening (Tonset), regional myocardial work, and segmental LV wall thickness (SWT) in patients treated with cardiac resynchronization therapy (CRT). We analysed 26 patients with sinus rhythm, non-ischaemic cardiomyopathy (63 ± 9 years, 69% male, QRS duration 174 ± 18 ms) and positive response to CRT (15% reduction in end-systolic volume). Longitudinal strain was obtained by 2D speckle-tracking echocardiography before and after [14.5 (7-29) months] CRT. Tonset and SWT were measured in 18 segments per LV. Segmental myocardial work was calculated from non-invasive segmental stress-strain loop area. Before CRT, Tonset was the shortest in septal and anteroseptal and the longest in lateral and posterior walls (P < 0.001) and not different after CRT (P = 0.733). Before CRT, s...
The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM... more The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/ sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling.
Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis... more Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis, and inflammation. Blocking the Wnt ligand Wnt5a prevents HF in animal models. However, the role of Wnt5a in human HF and its functions in cardiac cells remain unclear. Here, we investigated Wnt5a regulation in HF patients and its effects on primary mouse and human cardiac fibroblasts. Serum Wnt5a was elevated in HF patients and associated with hemodynamic, neurohormonal, and clinical measures of disease severity. In failing human hearts, Wnt5a protein correlated with interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1. Wnt5a messenger RNA (mRNA) levels were markedly upregulated in failing myocardium and both mRNA and protein levels declined following left ventricular assist device therapy. In primary mouse and human cardiac fibroblasts, recombinant Wnt5a dose-dependently upregulated mRNA and protein release of IL-6 and TIMP-1. Wnt5a did not affect β-catenin levels, but activated extracellular signalregulated kinase 1/2 (ERK1/2) signaling. Importantly, inhibition of ERK1/2 activation attenuated Wnt5a-induced release of IL-6 and TIMP-1. In conclusion, our results show that Wnt5a is elevated in the serum and myocardium of HF patients and is associated with measures of progressive HF. Wnt5a induces IL-6 and TIMP-1 in cardiac fibroblasts, which might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.
European Heart Journal - Cardiovascular Imaging, 2017
Clinical experience indicates that limited or no reverse left ventricular (LV) remodelling may no... more 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.
Journal of Cardiovascular Translational Research, 2017
In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involvin... more In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and noncanonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in endstage DCM, possibly mediating different effects on cardiac function. Keywords Dilated cardiomyopathy. Diastolic dysfunction. Delta-like Notch ligand 1 (DLL1). Delta-like 1 homologue (DLK1). Periostin (POSN). Notch pathway. Myocardial remodeling Abbreviations DCM Dilated cardiomyopathy DLL1 Delta-like Notch ligand 1 DLK1 Delta-like 1 homologue POSN Periostin Associate Editor Daniel P. Judge oversaw the review of this article Electronic supplementary material The online version of this article
This investigation assessed the ability of a non-invasive method to reproduce aortic root pressur... more This investigation assessed the ability of a non-invasive method to reproduce aortic root pressure waveform and pressures. An external pulse tracing of the subclavian artery was obtained simultaneously with direct aortic root pressures during routine left heart catheterization in 26 patients (aged 39-74 years) with various cardiovascular disorders. Indirect brachial arterial peak-systolic and nadir-diastolic pressures were obtained with oscillometry. The direct and indirect peak-systolic and nadir-diastolic pressures, were separately used to calibrate the pulse tracing. Adequate pulse tracing was obtained in 19 patients (73%). The waveforms agreed well with cross-correlation coefficients for systole and diastole of 0.98. The difference between the pulse trace and the direct pressure curve, when the first was calibrated with the peak-systolic and nadir-diastolic pressures of the latter on average was less than 1 mmHg for systole and diastole. At end-systole the mean difference was 5 mmHg. Oscillometric brachial arterial peak-systolic pressures were (mean +/- SD) 3 +/- 7 mmHg below the corresponding direct measurements, while diastolic pressures were 8 +/- 4 mmHg above. The difference between the pulse trace and the direct pressure curve, when the pulse trace was calibrated with oscillometric pressures, was at end-systole 6 +/- 6 mmHg and for mean arterial pressures 5 +/- 4 mmHg. Thus, the external subclavian arterial pulse tracing provides a non-invasive, clinically feasible access to the aortic root pressure waveform. With optimal calibration, good estimates of aortic root pressures throughout systole and diastole can be obtained, while end-systolic pressure tends to be slightly overestimated.
Journal of the American College of Cardiology, 2017
Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is... more Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is usually guided by brachial cuff blood pressure (BP), but questions have been raised regarding accuracy. This comprehensive analysis determined the accuracy of cuff BP and the consequent effect on BP classification compared with intra-arterial BP reference standards. Three individual participant data meta-analyses were conducted among studies (from the 1950s to 2016) that measured intra-arterial aortic BP, intra-arterial brachial BP, and cuff BP. A total of 74 studies with 3,073 participants were included. Intra-arterial brachial systolic blood pressure (SBP) was higher than aortic values (8.0 mm Hg; 95% confidence interval [CI]: 5.9 to 10.1 mm Hg; p < 0.0001) and intra-arterial brachial diastolic BP was lower than aortic values (-1.0 mm Hg; 95% CI: -2.0 to -0.1 mm Hg; p = 0.038). Cuff BP underestimated intra-arterial brachial SBP (-5.7 mm Hg; 95% CI: -8.0 to -3.5 mm Hg; p < 0.0001...
Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in ac... more Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in acute coronary syndromes. We evaluated the effect of the IL-6 receptor antagonist tocilizumab on coronary microvascular function and endothelial dysfunction measured by coronary flow reserve (CFR) and markers of endothelial cell activation in patients with non-ST-elevation myocardial infarction (NSTEMI). This substudy was part of a two-centre, double-blind, randomised, placebo-controlled trial evaluating the effect of a single dose of tocilizumab in NSTEMI. Markers of endothelial cell activation (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 and von Willebrand factor) were assessed in 117 patients. In 42 of these patients, 20 assigned to placebo and 22 to tocilizumab, we measured CFR. Blood samples were obtained at seven consecutive time points between day 1 and 3. CFR was measured by transthoracic echocardiography during hospitalisation and after 6 months. To...
European heart journal cardiovascular Imaging, Jan 25, 2017
The European Association for Cardiovascular Imaging (EACVI) has outlined the rationale for settin... more The European Association for Cardiovascular Imaging (EACVI) has outlined the rationale for setting appropriate use criteria (AUC) in cardiovascular (CV) imaging. Transthoracic echocardiography (TTE) is the most common imaging modality in CV disease and is a central tool in diagnosis, follow-up, management planning and intervention. The purpose of AUC is to inform referrers, both to avoid under-use, which may result in incomplete or incorrect diagnosis and treatment, and also over-use, which may delay correct diagnosis, lead to 'treatment cascade', and wastes resources. The first step in defining AUC for TTE in the adult has been for a panel of experts in echocardiography to review the evidence, guidelines, recommendations, and position papers from the European Society of Cardiology, EACVI and other specialist societies, and current state-of-the-art clinical practice. The attached document summarizes this work, which will be used to under-pin the development of AUC.
Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, Jan 5, 2017
The role of speckle-tracking echocardiography in the assessment of chronic aortic regurgitation (... more The role of speckle-tracking echocardiography in the assessment of chronic aortic regurgitation (AR) is not established. Load dependency may encumber the interpretation of strain measurements in the chronically overloaded left ventricle. The aim of this study was to investigate the mechanisms of left ventricular (LV) contraction patterns in asymptomatic patients with moderate to severe AR and preserved ejection fractions. In this prospective, cross-sectional study, 31 patients with moderate to severe AR, 15 elite endurance athletes, and 17 healthy control subjects were examined using three-dimensional speckle-tracking echocardiography. Global circumferential strain (GCS), global longitudinal strain (GLS), end-systolic circumferential wall stress (ESSc), end-systolic meridional wall stress (ESSm), and the wall stress ratio (ESSc/ESSm) were measured. LV end-diastolic volumes were similar in athletes and patients with AR and significantly larger than in healthy control subjects. Values...
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Papers by Svend Aakhus