Extracardiac Sources Research Articles

Role of the alarmin S100A9 in the pathogenesis of heart failure with preserved ejection fraction

Abstract Background A systemic low-grade inflammation induced by comorbidities is recognized to underlie heart failure (HF) with preserved ejection fraction (HFpEF)-specific remodelling. Recent evidence states that the innate immunity member S100A9, which is mainly present as the heterodimer S100A8/9, is an important contributor of sterile inflammation in the comorbidities of HFpEF, with adipose tissue being an important source. Though, its specific involvement in HFpEF has not been explored so far. Purpose The present study aimed to unravel the role of S100A9 in the pathogenesis of HFpEF via the two-hit HFpEF mouse model, S100A8/9 stimulation on murine left ventricle (LV) and C4 fibroblasts (Fb) and gene expression analysis of endomyocardial biopsy (EMB)-derived Fb from HFpEF and HF with reduced ejection fraction (HFrEF) patients. Methods Wild type (WT) C57BL/6JN or S100A9 knock-out (ko) mice were exposed to a high-fat diet (HFD) and L-NAME (1 g/L in drinking water) over 15 weeks. Controls received standard diet. LV function was characterized via conductance catheter measurements. At the day of sacrifice, the LV, spleen, blood, and adipose tissue were collected for subsequent analyses. In vitro, murine LV-derived Fb and C4 Fb were stimulated with the heterodimer S100A8/9. EMB-Fb from HFpEF and HFrEF patients were screened for S100A9 and downstream components of the NLRP3 inflammasome. Results WT HFD+L-NAME mice exhibited a preserved EF, combined with a reduced LV relaxation (dP/dtmin; p<0.01), elevated LV relaxation time (Tau; p<0.05), and impaired LV contractility (dP/dtmax; p<0.05), in parallel to a low-grade systemic inflammation evident by increased C-reactive protein levels. S100A9+, CD68+ and Ly6G+ cells, and CD68+ and Ly6G+ cells expressing S100A9 were increased in the LV, spleen and adipose tissue of WT HFD+L-NAME mice compared to WT mice on chow diet. Changes in LV function were less pronounced in S100A9ko HFD+L-NAME mice, which were characterized by lower systemic C-reactive protein levels, and lower presence of CD68+ and Ly6G+ cells in the LV, spleen and adipose tissue versus WT HFD+L-NAME mice, in the absence of S100A9. Moreover, S100A9ko HFD+L-NAME exhibited lower expression of pro-inflammatory and fibrosis-related genes versus WT HFD+L-NAME mice. Stimulation of murine LV-Fb and C4 Fb with S100A8/A9 increased the mRNA expression of the pro-inflammatory chemokines chemokine (C-C motif) ligand (CCL) 2 and CCL7, and the % of NLRP3-, ASC-, caspase 1-, and IL-1ß-expressing cells, respectively. Finally, mRNA expression of S100A9 and components of the NLRP3 inflammasome was higher in EMB-Fb of HFpEF versus HFrEF patients. Conclusion These data support that adipose tissue is an extra-cardiac source of S100A9 contributing to systemic low-grade inflammation. S100A8/9 in the heart can boost the inflammatory potential of cardiac fibroblasts, further supporting the pro-inflammatory role of S100A9 in the pathogenesis of HFpEF development.

Methods of diagnosing infective endocarditis including nuclear imaging techniques - a review

Introduction and the purpose of work Infective endocarditis (IE) is a disease diagnosed more and more often in recent years. Its treatment and diagnostics require a team of qualified specialists and are based on microbiological and imaging diagnostics. The purpose of this work is a summary and comparison of individual IE diagnostic methods, including their advantages and disadvantages. State of knowledge: Diagnosis of infective endocarditis relies on positive blood cultures to identify the microorganism and its drug sensitivity. Advanced methods like MALDI-TOF MS and MIC are used for identification. The first-line imaging diagnostic method for IE is echocardiography, which assesses structural and functional heart damage. Variants include transthoracic (TTE), transesophageal (TOE), three-dimensional TOE, and intracardiac echocardiography. Echocardiography should be performed immediately when IE is suspected. Computed tomography (CT) is crucial for diagnosing infective endocarditis (IE), particularly perivalvular and periprosthetic complications. Whole-body CT, including the brain, detects distant lesions and sources of bacteremia. CT is more accessible in emergencies and effective in spotting ischemic and hemorrhagic complications. CT angiography identifies mycotic aneurysms in the vascular system. It also detects extracardiac sources of bacteremia, aiding treatment and pre-surgery planning. Nuclear imaging is also important in diagnosing IE, especially prosthetic valve endocarditis (PVE) when echocardiography is inconclusive. 18F-fluorodeoxyglucose-PET/CT and SPECT/CT with labeled leukocytes are recommended. Conclusions: In addition to basic methods such as positive blood culture and echocardiography, there are more specialized methods that also allow for the assessment of treatment progress and prognosis.

Clinical efficacy of permanent internal mammary artery occlusion in chronic coronary artery disease: a double-blind, randomized, sham-controlled trial

Abstract Introduction Natural internal mammary artery (IMA) bypasses to the coronary circulation have been shown to act as extracardiac sources of myocardial blood supply, which has been found augmented by right IMA device occlusion. The goal of this randomized, sham-controlled trial was to test the efficacy of permanent right or left IMA device occlusion on symptoms of chronic coronary artery disease (CAD), on coronary artery occlusive blood supply, as well as on myocardial ischemia. Methods This was a prospective superiority trial in 100 patients with chronic CAD randomly allocated (1:1) to IMA permanent vascular device occlusion (verum group) or to IMA sham intervention (placebo group). The primary study endpoint was the change in treadmill exercise time (DET in seconds, s) during 6 weeks of follow-up after trial intervention. Secondary study endpoints were the changes in simultaneously obtained collateral flow index (CFI), and angina pectoris during a 1-minute proximal balloon occlusion of the coronary artery of interest. CFI is the ratio between simultaneous mean coronary occlusive divided by mean aortic pressure both subtracted by central venous pressure. Results In the verum and placebo group, exercise time changed from 398±176s to from 421±198s in the verum group (p=0.1745), and from 426±162s to 430±166s in the placebo group (p=0.55); DET was +23±116s and +4±120s, respectively (p=0.44). CFI change during follow-up was +0.022±0.061 in the verum and -0.039±0.072 in the placebo group (p<0.0001). Angina pectoris at follow-up during the coronary balloon occlusion for CFI measurement had decreased or disappeared in 20/48 patients of the verum group, and in 10/47 patients of the placebo group (p=0.0336). Conclusion Permanent IMA device occlusion tends to augment treadmill exercise time in response to heightened coronary artery occlusive blood supply, the fact of which is reflected by mitigated signs of myocardial ischemia.

Clinical Outcomes and Quality of Life after Patent Foramen Ovale (PFO) Closure in Patients with Stroke/Transient Ischemic Attack of Undetermined Cause and Other PFO-Associated Clinical Conditions: A Single-Center Experience.

The aim of this study was to assess clinical outcomes and quality of life after PFO closure in patients with previous stroke/TIA of undetermined cause and in patients with other complex PFO-associated clinical conditions. Between July 2009 and December 2019 at our University Cardiology Department, 118 consecutive patients underwent a thorough diagnostic work-up including standardized history taking, clinical evaluation, full neurological examination, screening for thrombophilia, brain magnetic resonance imaging (MRI), ultrasound-Doppler sonography of supra-aortic vessels and 24 h ECG Holter monitoring. Anatomo-morphological evaluation using 2D transthoracic/transesophageal echocardiography (TTE/TEE) color Doppler and functional assessment using contrast TTE (cTTE) in the apical four-chamber view and contrast transcranial Doppler (cTCD) using power M-mode modality were performed to verify the presence, location and amount of right-to-left shunting via PFO or other extracardiac source. Completed questionnaires based on the Quality-of-Life Short Form-36 (QoL SF-36) and Migraine Disability Assessment (MIDAS) were obtained from the patients before PFO closure and after 12 months. Contrast TTE/TEE and cTCD were performed at dismission, 1, 6 and 12 months and yearly thereafter. Brain MRI was performed at 1-year follow-up in 54 patients. Transcatheter PFO closure was performed in 106 selected symptomatic patients (mean age 41.7 ± 10.7 years, range 16-63, 65% women) with the following conditions: ischemic stroke (n = 23), transient ischemic attack (n = 22), peripheral and coronary embolism (n = 2), MRI lesions without cerebrovascular clinical events (n = 53), platypnea-orthodeoxia (n = 1), decompression sickness (n = 1) and refractory migraine without ischemic cerebral lesions (n = 4). The implanted devices were Occlutech Figulla Flex I/II PFO (n = 99), Occlutech UNI (n = 3), Amplatzer PFO (n = 3) and CeraFlex PFO occluders (n = 1). Procedures were performed under local anesthesia and rotational intracardiac monitoring (Ultra ICE) alone. The devices were correctly implanted in all patients. The mean fluoroscopy time was 15 ± 5 min (range = 10-45 min) and the mean procedural time was 55 ± 20 min (range = 35-90 min). The total occlusion rate at follow-up (mean 50 months, range 3-100) was 98.1%. No recurrent neurological events were observed in the long-term follow-up. The data collected in this study demonstrate that percutaneous PFO closure is a safe and effective procedure, showing long-term prevention of recurrent cerebrovascular events, significant reduction in migraine symptoms and substantial improvement in quality of life.

PO-01-107 INTRA-CARDIAC SPINDLE CELL CARCINOMA FOLLOWING CATHETER ABLATION OF ATRIAL FIBRILLATION AND LEFT ATRIAL APPENDAGE CLOSURE

Spindle cell carcinoma (SpCC), a type of squamous cell carcinoma (SCC), is a rare tumor with features similar to sarcoma that often arises from the respiratory system. Myocardial involvement of these tumors has not been described. We present a case of metastatic SpCC diagnosed through routine transesophageal echocardiography (TEE) following left atrial appendage occlusion (LAAO). To describe a rare occurrence of metastatic SpCC diagnosed through routine TEE following LAA occlusion. NA A 61 year old male with a history of coronary artery disease and heart failure presented with persistent symptomatic atrial fibrillation (AF) despite anti-arrhythmic therapy. We performed pulmonary vein isolation (PVI) and during intubation a laryngeal mass was noted. He was diagnosed with T2N0M0 sarcomatoid SCC and had surgery, radiation and chemotherapy (cisplatin). At that time, he was felt to have a favorable 5 year survival prognosis. Six months later he represented with symptomatic AF and underwent repeat PVI. Due to concerns regarding bleeding risk, LAAO was later performed. During follow up TEE at day 45, a new cystic lesion arising from the posterior left atrium and a 2x3cm heterogenous mass associated with the interatrial septum was noted (Figure 1 A-D). CT scan showed new mediastinal masses with extension into the left atrium in the region treated with radiofrequency ablation (Figure 1 E-H). Biopsy revealed SpCC consistent with the initial laryngeal mass. Tumor extending from the perihilar mass and in the fossa ovalis, given the proximity of prior work and prior transseptal puncture, raises the concern for inadvertent iatrogenic spread of tumor and that catheter manipulation facilitated invasion into the LA with the pedunculated mass and seeded the septum. The patient unfortunately continued to decline clinically and shortly thereafter transitioned to comfort care and passed away. We present a case of persistent symptomatic AF in which laryngeal SpCC was diagnosed during initial PVI and rapidly progressive metastatic SpCC diagnosed via TEE in follow up after LAAO. This presentation is concerning for inadvertent iatrogenic spread of tumor from an extracardiac source through PVI. SpCC is more aggressive than typical SCC, however rapid invasion through the chest wall, lung and myocardium within 1.5 months is extremely rare. While primary spindle cell sarcoma of the myocardium has been reported, to our knowledge we report the first case of metastatic SpCC to the heart.

FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure.

Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling. To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters. Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4-1040.3] pg/mL, n=40; controls: 146.0 [86.3-205.7] pg/mL, n=20, P=1.9×10-5). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion. Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.

Screening echocardiography for suspicion of infective endocarditis: Are all the requests justified according to the Guidelines of the European Society of Cardiology (ESC)?

Echocardiograms are largely performed for suspicion of infective endocarditis (IE), and usually have a poor diagnosis yield, especially if there is a low clinical probability. The ESC Guidelines of 2009 and 2015 proposed very large criteria that define clinical suspicion of IE and justify an echocardiogram request. We studied if the patients referred for suspicion of IE had clinical criteria who respected the ESC Guidelines for screening echocardiography, and we tried to identify the factors associated with the diagnosis of IE. We retrospectively examined all the transthoracic echocardiogram (TTE) and transoesophageal echocardiogram (TOE), performed for suspicion of IE between January 2017 and December 2017 in the University Hospital of Nîmes, France. Three hundred and fifty patients were referred for a suspicion of IE. Two hundred and eighty three (80,9%) TTEs and 67 (19,1%) TOEs were performed in first intention. A second exam was performed in 99 (28,3%) patients: a TTE for 56 patients and a TOE for 43 patients. For 61 (17,4%) patients, the echocardiogram request was not appropriate according to referral of the ESC Guidelines, with no sufficient clinical criteria that may allow to suspect an IE. None of these 61 patients was diagnosed with an IE. IE was finally diagnosed in 51 (14,6%) patients. The significant independent factors associated with the diagnosis of IE were: positive blood culture (OR = 26,6 IC95% = [3,6–195,9] P = 0,001), embolic phenomena (OR = 2,4 IC95% = [1,3–4,5] P = 0,005), previous valvular heart disease (OR = 2,7 IC95% = [1,1–6,7] P = 0,003) and sepsis in absence of an extra cardiac source of infection (OR = 12,6 IC95% = [4,4–35,9] P < 0,001) (Fig. 1). One fifth of the patients referred for an echocardiogram had no sufficient clinical criteria to suspect an IE according to the referral of the ESC Guidelines, and none of them was diagnosed with an IE. The use of these criteria for screening echocardiography for suspicion of IE may avoid many unnecessary echocardiograms.

Treatment Options for Pulmonary Atresia/VSD/MAPCAs

This review provides an up to date overview of the treatment options for newborns with pulmonary atresia/VSD/MAPCAs. It answers the question of how best to diagnose and formulate a surgical plan for this diverse and heterogeneous patient population. The surgical repair of patients with pulmonary atresia/VSD/MAPCAs can be performed safely with excellent results as a single stage procedure and in the neonatal period in specific circumstances. Pulmonary atresia/VSD/MAPCAs is a complex and varied lesion. Its clinical presentation and management vary between patients and is mainly dictated by the anatomic characteristics of the major aortopulmonary collaterals which constitute the extracardiac sources of pulmonary blood flow. A rigorous evaluation of the patient’s anatomy is mandatory. Precise surgical planning is a prerequisite and exact surgical execution is required for a successful patient outcome.

ISCHEMIC STROKE IN A PATIENT WITH A WATCHMAN DEVICE: WHAT'S THE LEAK GOT TO DO WITH IT?

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: The prevention of stroke is a significant challenge in patients with atrial fibrillation. The advent of the WATCHMAN device has provided a much needed alternative for patients in whom long term anticoagulation is not appropriate. However, the efficacy and safety of this device has not been well studied. CASE PRESENTATION: 82-year-old man presented with visual disturbances and unsteady gait. He underwent MRI of the brain which revealed an acute right occipital infarction which appeared embolic in origin. He had a history of chronic atrial fibrillation requiring anticoagulation and had undergone successful left atrial appendage (LAA) closure via placement of WATCHMAN device 6 months prior. Anticoagulation was discontinued post-implant as per protocol. In the setting of an acute embolic stroke with a WATCHMAN device in place, further workup was advised. To ascertain the source of the embolic stroke, further imaging was undertaken. CT angiogram of the head, neck, and chest did not show any extracardiac source of thromboembolism. Transesophageal echocardiogram (TEE) was negative for intracardiac thrombus, however, a 5 mm residual leak was noted at the edge of the WATCHMAN implant. In the absence of any other source, the patient’s stroke was presumed to be cardioembolic and likely originating in the LAA, given the leak around the implant. Dual antiplatelet therapy was resumed with the intention of initiating anticoagulation once he recovered from his acute stroke. DISCUSSION: Left atrial appendage occlusion (LAAO) is a novel procedure that is becoming more commonplace. It is indicated for patients with atrial fibrillation at high risk for cardioembolic stroke but also have contraindications to anticoagulation. However, LAAO devices are not without complications. Currently, the WATCHMAN implant is the only FDA approved LAAO device on the market. Trial data suggests a higher risk of ischemic strokes in patients who have undergone WATCHMAN implant. However, there is limited awareness and understanding of this complication in clinical practice. Up to 14% of patients can develop device-related thrombi (DRT) and up to 3.7% of patients can have device embolization. Because the incidence of DRT is rare, it is difficult to identify risk factors that may predict individuals at risk of developing them. Current guidelines recommend screening TEE at 45 days, however, most DRT are detected after more than 45 days. This implies that current recommendations may be inadequate for preventing DRT in at-risk patients. CONCLUSIONS: As LAA closure devices become more prevalent, there is a growing need for re-assessing their efficacy and establishing guidelines for assessing device function. Furthermore, identification of sub-groups that are at higher risk for delayed complications will help with patient selection in the future. Reference #1: Moussa Pacha H, Al-Khadra Y, Soud M, Darmoch F, Moussa Pacha A, Alraies MC. Percutaneous devices for left atrial appendage occlusion: A contemporary review. World J Cardiol. 2019;11(2):57-70. Reference #2: Dukkipati S.R., Kar S., Holmes D.R., et al: Device-related thrombus after left atrial appendage closure: incidence, predictors, and outcomes. Circulation 2018; 138: pp. 874-885. Reference #3: Alkhouli M., Busu T., Shah K., Osman M., Alqahtani F., and Raybuck B.: Incidence and clinical impact of device-related thrombus following percutaneous left atrial appendage occlusion: a meta-analysis. J Am Coll Cardiol EP 2018; 4: pp. 1629-1637. DISCLOSURES: No relevant relationships by basma al-bast, source=Web Response No relevant relationships by Mirza Ali, source=Web Response No relevant relationships by Abdisamad Ibrahim, source=Web Response No relevant relationships by Abhishek Kalidas Kulkarni, source=Web Response No relevant relationships by Nitin Tandan, source=Web Response

Abstract 567: Fgf21 as a Biomarker for Metabolic Stress in Heart Failure

FGF21, an important metabolic regulator, has recently been suggested as a biomarker for heart failure (HF). FGF21 is involved in the integrated mitochondrial stress response, and has been shown to be upregulated with mitochondrial DNA damage, which occurs more frequently in dilated cardiomyopathy. In this study, we investigated whether FGF21 can be used as a biomarker for metabolic stress in HF. We collected blood and cardiac tissue samples from ischemic and non-ischemic HF patients who have undergone VAD transplantation. We also collected blood and tissue from mice with HF due to 1) combination of transverse aortic constriction and coronary artery ligation (TAC+Lig) or 2) cardiac-specific knockout of the mitochondrial transcription factor A (Tfam). Serum FGF21 levels were measured using Enzyme-linked immunosorbent assay (ELISA). Messenger RNA was extracted from the tissue and FGF21 gene expression was measured using real-time quantitative PCR (qPCR). Immunohistochemical staining was performed on tissue sections (either paraffin embedded or frozen) to observe FGF21 levels. Serum FGF21 was elevated in human HF patients compared to healthy controls, as well as in both mouse models of HF. In human patients, cardiac FGF21 gene expression was upregulated 2.2-fold compared to donors. In the TAC+Lig mouse model we observed a 3.37-fold increase, while the Tfam knockout model which has severe mitochondrial damage exhibited a 218-fold increase in cardiac FGF21 gene expression. Further qPCR assays revealed changes in FGF21 gene expression in the liver and white fat of TFAM-KO, indicating metabolic stress on other organs resulting from HF. In conclusion, serum FGF21 is elevated in multiple models of HF, and appears to have both cardiac and extra cardiac sources. Future work will investigate 1) whether there is a correlation between FGF21 levels and mitochondrial damage, and 2) the signaling pathway resulting in metabolic stress to other organs in HF.

The exocrine pancreas is an extracardiac source of atrial natriuretic peptide.

Previous studies have shown that atrial natriuretic peptide (ANP) regulates exocrine pancreatic function in health and disease. As extracardiac sources of ANP have been identified and ANP-like immunoreactivity has been reported in the exocrine pancreas, in the present work we sought to establish whether ANP was produced in the rat exocrine pancreas and if conditions like fasting/feeding or acute pancreatitis were reflected on ANP expression. By using RT-PCR, immunoblotting, and immunofluorescence microscopy assays, it was found that both mRNA and protein ANP were present in the acinar cells of the exocrine pancreas. The amount of ANP in the pancreas was lower in than the atrium but similar to other tissues like the kidney and liver. Immunogold labeling electron microscopy studies revealed that ANP was localized in zymogen granules and the endoplasmic reticulum suggesting local synthesis and package into granules. ANP protein expression was significantly increased not only in fasting but also in acute pancreatitis, the latter probably related to impaired secretion. Natriuretic peptide receptor type C which mediates ANP biological effects in the exocrine pancreas was also present in acinar cells and its expression did not change with either fasting or acute pancreatitis. Present findings show that the exocrine pancreas is a relatively important extracardiac source of ANP and further support previous studies strongly suggesting the active role of the peptide in pancreatic physiology and pathophysiology.

Tadeusz Stefan Kurkiewicz (1885-1962) – His Important Contribution to Contemporary Cardiology

Abstract Tadeusz Stefan Kurkiewicz (1885-1962) belongs to the well-known Polish histologists and embryologists. His scientific activity started in the Department of Biology and Embryology of the Jagiellonian University in Cracow, which was chaired by professor Emil Godlewski (1875-1944), famous Polish embryologist. Between years 1908-1911, under supervision of the pioneer of the Polish histology, professor Stanisław Maziarski (1873-1959) T. Kurkiewicz continued researches in the Department of Histology of the Jagiellonian University. In 1909 he published results of studies on the development of cardiac muscle in the chick and on the basis of this publication on July 21, 1911 Tadeusz Kurkiewicz received Ph.D. from the Jagiellonian University. Between 1922 and 1959 (with the exception of the period of German occupation) Tadeusz Kurkiewicz was the head of the Department of Histology and Embryology of the Faculty of Medicine of the Poznań University and Academy of Medicine in Poznań (at present: Poznań University of Medical Sciences). His Ph.D. thesis demonstrated that the epicardium originates from pericardial villi, it means from extracardiac source. This great scientific achievement has been confirmed by recent studies. In this article we present curriculum of Tadeusz Kurkiewicz and impact of his discovery on contemporary cardiology.

Abstract 12645: Coronary Sinus Biomarker Assessments in Non-ST Elevation Acute Coronary Syndrome: Systemic or Local Cardiac Release of High Sensitivity C-Reactive Protein?

Introduction: High sensitivity C-reactive protein (hsCRP) is frequently elevated in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). However, controversy remains regarding the origin of hsCRP. Reported theories vary from a systemic increase in inflammatory status, to a more local process. Purpose: To assess concentrations of hsCRP in patients with ongoing NSTE-ACS using multiple sampling sites, to enable measurement of systemic or local changes. Methods: 46 Troponin positive NSTE-ACS patients with significant coronary artery disease were included. Systemic arterial and venous blood was obtained, and right sided catheterization was performed to sample blood from the coronary venous system (CVS). In suitable patients, an additional blood sample was collected from the culprit coronary artery distal to the culprit lesion. Six hours post procedure blood was obtained from the systemic venous circulation. hsCRP concentrations were compared between the sampling sites. Results: The median hsCRP concentrations in the systemic arterial and venous blood were high and not significantly different. hsCRP concentrations in the CVS were significantly lower (table).The median hsCRP concentrations between blood collected from the culprit coronary artery distal to the culprit lesion and the systemic arterial circulation were not significantly different (4.56mg/L to 4.40mg/L, respectively, n=14; p=0.551). Systemic hsCRP concentrations six hours post procedure were significantly higher (5.66mg/L vs 4.86mg/L; p&lt;0.001). Conclusion: In this series of patients with ongoing NSTE-ACS a decrease in hsCRP from the systemic circulation to the CVS was observed. This observation, combined with similar concentrations proximal and distal to the culprit and higher systemic concentrations six hours post procedure favors an extracardiac source of hsCRP.

Pathophysiological aldosterone levels modify the secretory activity of cardiac progenitor cells

Cardiac progenitor cells (CPCs) trigger regenerative processes via paracrine mechanisms in response to changes in their environment. In the present study we explored alterations in the secretory activity of CPCs induced by raised aldosterone levels symptomatic for heart failure. The cytokine profile of the supernatant of CPCs that were treated with the mineralocorticoid showed an induction of interleukin-6 secretion. Mass spectrometric analyses revealed an increase in the abundance of secreted proteins associated with regeneration and cell migration like gelsolin and galectin-1. Differential regulation of proteins associated with the extracellular matrix further points to an activation of cell migration. In response to supernatant, migration and proliferation were induced in CPCs, indicating a potential role of paracrine factors in the activation of CPCs from other regions of the heart or extra-cardiac sources. Changes in the secretory activity of CPCs might aim to compensate for the detrimental actions of aldosterone in heart failure.

Microsurgical Procedures for Studying the Developmental Significance of the Proepicardium and Epicardium in Avian Embryos: PE-Blocking, PE-Photoablation, and PE-Grafting

The epicardium is the outer skin of the mature vertebrate heart. Its embryonic origin and its possible roles in the developing and mature heart did not receive much recognition during the 19th and most of the 20th century. During the past 25 years, however, the epicardium came into the focus of developmental biology and regenerative medicine. Clinical researchers usually prefer genetically modified mouse models when they want to gain insight into developmental or pathological processes. The story of research on the embryonic epicardium, however, nicely demonstrates the value of non-mammalian species, namely avian species, for elucidating fundamental processes in embryonic and fetal development. Studies on chick and quail embryos have not only led to the identification of the primarily extracardiac source of the epicardium—presently called the proepicardium (PE)—they have also significantly contributed to our current knowledge about the developmental significance of the embryonic epicardium. In this review article, I describe three “classical” microsurgical experiments that have been developed for studying the developmental significance of the PE/epicardium in avian embryos (mechanical PE-blocking, PE-photoablation, orthotopic PE-grafting). Furthermore, I show how these microsurgical experiments have contributed to our current knowledge about the roles of the PE/epicardium in cardiac development. There are still some unsolved aspects in the physiology of the developing epicardium, which may be clarified with the aid of these “classical” microsurgical experiments.

The Origin and Arrhythmogenic Potential of Fibroblasts in Cardiac Disease

Fibroblasts play a major role in normal cardiac physiology and in the response of the heart to injury and disease. Cardiac electrophysiological research has primarily focused on the mechanisms of remodeling that accompany cardiac disease with an emphasis on myocyte electrophysiology. Recently, there has been increasing interest in the potential role of fibroblasts in cardiac electrophysiology. This review focuses on the arrhythmia mechanisms involving interactions between myocytes and fibroblasts. We also discuss the available evidence supporting the contribution of intracardiac and extracardiac sources to the fibroblast and myofibroblast populations in diseased hearts.

Cardiac resident progenitor cells: evidence and functional significance

This editorial refers to ‘Higher frequencies of BCRP+ cardiac resident cells in ischaemic human myocardium’, by M.Y. Emmert et al. , doi:10.1093/eurheartj/ehs156 It has been estimated that a serious myocardial infarction (MI) results in the loss of ∼1 billion functional cardiomyocytes, which are replaced with a fibrous scar, frequently leading to heart failure. Experimental data demonstrate that the mitotic renewal in the human myocardium exists but at a very low rate: 1% annually at the age of 25 and 0.45% at the age of 75.1 With this turnover rate, most cardiomyocytes will never be exchanged during a normal life span. Although the renewal rate may increase somewhat after injury, the heart itself is not able to effect large-scale cardiac regeneration. Thus, stem cell-based therapy may be a realistic strategy for providing a source of new functional cardiomyocytes. Additionally, stem cells may promote tissue healing through paracrine mechanisms. Regenerative stem cells may be derived from extracardiac sources as well as from the heart itself. Over the past decade, extensive studies have provided us with evidence that progenitor cells are present in the adult heart. In mice, cells expressing the stem cell factor receptor c-Kit,2 stem cell antigen-1 (Sca-1),3 and transcription factor islet-1 (Isl-1),4 as well as side population (SP) cells5 have been identified as cardiac resident progenitor cells (CRPCs) due to their ability to differentiate into cardiomyocytes both in vivo and in vitro . Following the animal studies, a series of studies by several independent groups have suggested that CRPCs also exist in adult or postnatal hearts of humans ( Figure 1 ),4,6–9 which are also identified by the expression of c-Kit, Sca-1, and Isl-1. In addition, cardiospheres cultured from human heart biopsies contain CRPCs and can proliferate in vitro (not addressed in …

Generation, Characterization, and Potential Therapeutic Applications of Cardiomyocytes from Various Stem Cells

Heart failure is one of the leading causes of death worldwide. Myocardial cell transplantation emerges as a novel therapeutic strategy for heart failure, but this approach has been hampered by severe shortage of human cardiomyocytes. We have recently induced mouse embryonic stem cells to differentiate into embryoid bodies and eventually, cardiomyocytes. Here, we address recent advancements in cardiomyocyte differentiation from cardiac stem cells and pluripotent stem cells. We highlight the methodologies, using growth factors, endoderm-like cell cocultures, small molecules, and biomaterials, in directing the differentiation of pluripotent stem cells into cardiomyocytes. The characterization and identification of pluripotent stem cell-derived cardiomyocytes by morphological, phenotypic, and functional features are also discussed. Notably, increasing evidence demonstrates that cardiomyocytes may be generated from the stem cells of several tissues outside the cardiovascular system, including skeletal muscles, bone marrow, testes, placenta, amniotic fluid, and adipose tissues. We further address the potential applications of cardiomyocytes derived from various kinds of stem cells. The differentiation of stem cells into functional cardiomyocytes, especially from an extra-cardiac stem cell source, would circumvent the scarcity of heart donors and human cardiomyocytes, and, most importantly, it would offer an ideal and promising cardiomyocyte source for cell therapy and tissue engineering in treating heart failure.

Contribution of circulating biomarkers to unravel the role of extracellular matrix in hypertensive cardiac remodelling

Contribution of circulating biomarkers to unravel the role of extracellular matrix in hypertensive cardiac remodelling

Cardiac Cell Therapies: The Next Generation

Although significant advances have been made in terms of pharmacological, catheter-based, and surgical palliation, heart failure remains a fatal disease. As a curative concept, regenerative medicine aims at the restoration of the physiologic cellular composition of diseased organs. So far, clinical cardiac regeneration attempts have only been moderately successful, but a better understanding of myocardial cell homeostasis and somatic as well as embryonic stem cell biology has opened the door for the development of more potent therapeutic cardiac regeneration strategies. Accumulating evidence indicates that the postnatal mammalian heart retains a pool of tissue-specific progenitor cells and is also repopulated by cells from extracardiac sources. However, this intrinsic myocardial regeneration potential clearly needs to be augmented by either manipulation of the cell cycle of differentiated cells, activation of resident cardiac progenitor cells, and/or the transplantation of exogenous cells. This review summarizes the recent developments in cardiac regenerative medicine, many of which may find their way into the clinical setting in the foreseeable future.