Cardiac Architecture Research Articles

Application of micro-computed tomography with iodine staining to cardiac imaging, segmentation, and computational model development.

Micro-computed tomography (micro-CT) has been widely used to generate high-resolution 3-D tissue images from small animals nondestructively, especially for mineralized skeletal tissues. However, its application to the analysis of soft cardiovascular tissues has been limited by poor inter-tissue contrast. Recent ex vivo studies have shown that contrast between muscular and connective tissue in micro-CT images can be enhanced by staining with iodine. In the present study, we apply this novel technique for imaging of cardiovascular structures in canine hearts. We optimize the method to obtain high-resolution X-ray micro-CT images of the canine atria and its distinctive regions-including the Bachmann's bundle, atrioventricular node, pulmonary arteries and veins-with clear inter-tissue contrast. The imaging results are used to reconstruct and segment the detailed 3-D geometry of the atria. Structure tensor analysis shows that the arrangement of atrial fibers can also be characterized using the enhanced micro-CT images, as iodine preferentially accumulates within the muscular fibers rather than in connective tissues. This novel technique can be particularly useful in nondestructive imaging of 3-D cardiac architectures from large animals and humans, due to the combination of relatively high speed ( ~ 1 h/per scan of the large canine heart) and high voxel resolution (36 μm) provided. In summary, contrast micro-CT facilitates fast and nondestructive imaging and segmenting of detailed 3-D cardiovascular geometries, as well as measuring fiber orientation, which are crucial in constructing biophysically detailed computational cardiac models.

Immunophenotypic alterations in resident immune cells and myocardial fibrosis in the aging rhesus macaque (Macaca mulatta) heart.

The rhesus macaque (Macaca mulatta) is used extensively in translational biomedical research and drug development studies and is an important model of aging. Macaques often develop myocardial fibrosis with age, which can result in the loss of normal cardiac architecture with the expansion of the extracellular matrix and deposition of collagen. The etiology and pathogenesis of this pernicious process is poorly understood. Cardiac fibrosis was assessed using histologic and immunohistochemical techniques in cardiac tissue sections from 34 rhesus macaques. Overall left ventricular and left ventricular mid-myocardial interstitial/perivascular fibrosis were positively correlated with age (r = .6522, p < .0001 and r = .4704, p = .005, respectively). When divided into young (mean = 2.8 years), middle-aged (mean = 17.5 years), and advanced age (mean = 29.2 years) groups, immunophenotypic characterization of antigen presenting cells revealed differential expression of CD163 and DC-SIGN between the young and middle-aged groups compared to the advanced age group (p < .0001). HAM-56 expression decreased significantly in the advanced age cohort (p = .0021). The expression of CD8, CD163, and DC-SIGN correlated positively with age (r = .3999, p = .0191; r = .5676, p = .0005; r = .5245, p = .0014, respectively). These results show the importance of myocardial fibrosis as a common age-related pathology and additionally, alterations in T cell, macrophage, and dendritic cell phenotype in rhesus macaque myocardium are associated with age but unassociated with the fibrosis.

P-1352 - Improvement of the link between cardiac vagal influence and delta sleep in sahs by long-term nCPAP treatment

Introduction Numerous cardiovascular events are related to sleep apnea-hypopnea syndrome (SAHS). Several studies reported, in SAHS patients, increased cardiac sympathic influence and altered link between cardiac vagal activity and delta sleep EEG. Nevertheless, short-term nasal CPAP (nCPAP) treatment regulates cardiac sympatho-vagal balance and sleep architecture. Objectives We tested that long-term nCPAP treatment improves the link between cardiac vagal influence and delta sleep EEG across the night. Aims Long-term nCPAP treatment could improve the link between heart rate variability (HRV) and sleep to prevent occurrence of cardiovascular events. Methods Cardiac activity and sleep of 8 middle-aged men suffering from SAHS were recorded before and after at least 6 months of nCPAP treatment. They were matched for sex, age, caffeine, nicotine and alcohol consumption with 14 healthy men. All subjects were free of somatic and psychiatric disorders as well as medication. Sleep architecture, spectral components of HRV and delta power band were calculated across the first three NREM-REM cycles as well as a coherence analysis between cardiac vagal influence and delta sleep EEG. Results AHI was 63.5 ± 22.9 vs 5.5 ± 4.4 events/hour after 47 ± 34 months of nCPAP treatment (mean± standard deviation). Awake, NREM and REM sleep durations were similar between groups as well as spectral HRV components. Coherence analysis revealed decreased gain value for untreated patients in comparison to controls while difference disappeared with nCPAP treatment. Conclusions Long-term nCPAP treatment improves the link between cardiac vagal influence and delta sleep even in the absence of altered HRV.

Late Effects of Renal Transplantation on Endothelial Functions and Cardiac Morphology

Background Endothelial dysfunction is common in patients undergoing hemodialysis (HD), and cardiovascular morbidity and mortality are higher in these patients. In this study, we evaluated the late posttransplantation effects of cyclosporine and tacrolimus on endothelial function, inflammation, and cardiac architecture. Methods The study included 12 patients undergoing hemodialysis (group 1); 22 renal transplant recipients, of which 13 were receiving cyclosporine therapy (group 2) and 9 were receiving tacrolimus therapy (group 3); and 12 healthy control individuals (group 4). Kidney recipients were included if the transplantation procedure had been performed at least 1 year before the study. Asymmetric dimethylarginine, C-reactive protein, carotid intima-media thickness, left ventricular posterior wall thickness, interventricular septal thickness, left ventricular muscle mass index, flow-mediated dilation, and nitroglycerine-induced dilation of the brachial artery were evaluated. Results Serum asymmetric dimethylarginine, C-reactive protein, carotid intima-media thickness, left ventricular posterior wall thickness, interventricular septal thickness, and left ventricular muscle mass index values were significantly higher in patients undergoing HD than in the other 3 groups ( P < .05), whereas percent change in flow-mediated dilation and nitroglycerine-induced dilation of the brachial artery was significantly lower ( P < .05). Conclusion Patients undergoing HD demonstrate endothelial dysfunction. In the late posttransplantation period, kidney recipients seem to have similar endothelial function and cardiac architecture as in the healthy population. This result may explain the reduction in cardiovascular morbidity and mortality after transplantation in patients undergoing HD. Tacrolimus and cyclosporine have similar effects on endothelial function.

Ventricular Torsion and Untwisting: Further Insights into Mechanics and Timing Interdependence: A Viewpoint

Ventricular torsion and untwisting are essential for normal ventricular function and their mechanisms are related to the temporal responses of the helical and circular muscle fibers that comprise cardiac architecture. Explanation of the presystolic isovolumic contraction (IVC) period is essential for analysis of these interactions. Structural and imaging studies by magnetic resonance, speckle tracking, velocity vector encoding, and sonomicrometer crystals are described to define why and how different muscular components contract asynchronously. Mechanical and functional relationships are described for pre-systolic IVC, torsion, postejection isovolumic interval, and rapid and slow filling. Circular fibers dominate to cause pre- and posttwisting global counterclockwise and clockwise movement, and helical fibers govern torsion whereby the base rotates clockwise and apex counterclockwise; untwisting cannot begin until torsion is completed. Prolonged torsion extends into the postejection isovolumic interval and delays untwisting, and is caused by prolonged contraction of the right-handed helical arm or descending segment of the helical ventricular myocardial band that narrows the ∼80 ms "timing hiatus" between end of shortening of the descending and the ascending segment or left-handed arm of the helical muscle. Longer torsion duration by this mechanism becomes the common theme for unbalanced torsion and untwisting in diastolic dysfunction, physiological, structural, and electrical disease processes, whose management may be guided by changing the interconnected reasons for these adverse mechanical and timing factors.

EFFECTS OF DEEP-SEA WATER ON CARDIAC ABNORMALITY IN HIGH-CHOLESTEROL DIETARY MICE

ABSTRACT Our recent studies indicated that electrodialysed deep-sea water (ED-DSW) revealed the cardiovascular health effects, such as hindrances of the dietary-induced evaluation of total cholesterol (TC), triglyceride (TG) and nonhigh-density-lipoprotein cholesterol (HDL-C), as well as improvement of HDL-C/non-HDL-C ratio and blood pressure. In the current study, we further revealed the beneficial effects of ED-DSW on high-cholesterol dietary mice by reducing abnormal cardiac architecture, apoptosis and enhancing insulin-like growth factor-1 receptor (IGF-1R) cardiac survival signaling compared with those mice that were treated with distilled water, reverse osmosis (RO)-DSW or 10% (v/v) dilution with ddH2O (10% DSW). These findings further clarified the possible mechanisms of cardiac protective effects of ED-DSW and might suggest ED-DSW as an ingredient of cardiovascular health food in some niche markets. PRACTICAL APPLICATIONS Deep-sea water (DSW) has been applied on several fields including aquaculture, agriculture, food processing, cosmetics and medicine. Recently, we have indicated that high-cholesterol dietary mice drinking electrodialysed DSW (ED-DSW) showed decreased serum lipids, blood pressure and improving blood cholesterol profile. In this study, we further demonstrated the beneficial effects of ED-DSW on high-cholesterol dietary mice by reducing abnormal cardiac architecture, apoptosis in left ventricle and increasing cardiac survival signaling, such as insulin-like growth factor-1 receptor, phosphoinositide-3-kinases and p-AKT/AKT ratio. Altogether, these findings indicated that ED-DSW revealed the cardiac protective effects and might be suggested as an ingredient of cardiovascular health food in a variety of niche markets.

Evaluation of Cardioprotective Effect of 3,5,3′-Tri-iodo-L-thyronine in Isoproterenol-Induced Cardiotoxicity

T3 (3,5,3′-triiodothyronine) has drawn relatively little attention in relation to cardiovascular (CVS) diseases. The present study was designed to evaluate the cardioprotective action of T3 in isoproterenol-(ISO-) induced cardiac toxicity. Female Wistar rats were exposed with ISO (100 mg/kg, body weight, subcutaneously) for 2 days at the interval of 24 h followed by T3 (3 μg/kg, body weight, orally) treatment for 3 days. Positive control rats received only ISO (100 mg/kg, body weight, subcutaneously) for 2 days at the interval of 24 hrs. Control group animals received normal saline as a vehicle. As expected, ISO-induced significant changes were observed in low-density lipoprotein, total cholesterol, ALT, CK-MB to TCK ratio, and prolongation of QT interval in electrocardiogram, which is toward normalization after T3 treatment. Lower heart weight, upregulation of cardiac myosin heavy chain alpha (MHC-α), and reduced inflammatory cell infiltration, myonecrosis, vacuolar changes, and a trend toward normal cardiac muscle fiber architecture in microscopic examination of cardiac tissue further support the cardioprotective effect of T3.

Assessment of coronary blood flow with computed tomography and magnetic resonance imaging

Noninvasive assessment of myocardial blood flow (MBF) has proved to be useful for the diagnosis and risk stratification of patients with known or suspected coronary artery disease. However, the relationship between myocardial perfusion abnormalities and coronary atherosclerosis is complex, and one is not necessarily predictive of the other. 1,2 An example of this is in diminished MBF, which can also be caused by microvascular dysfunction without correlation to flow-limiting epicardial lesions. 3 In contrast to this, normal MBF can persist despite severe coronary disease due to the presence of collateral blood flow. Coronary angiography and myocardial perfusion imaging has become complementary, rather than substitutive methods to evaluate coronary artery disease. 4 Single-photon emission computed tomography (SPECT) represents the most widely applied methods for myocardial perfusion assessment in clinical practice today, while positron emission tomography (PET) is the most reliable method for noninvasive absolute MBF quantification. In recent years, cardiac magnetic resonance (MR) and cardiac computed tomography (CT) have emerged as promising techniques for MBF assessment. In these tomographic imaging techniques, measurement of MBF is based upon tissue enhancement of an intravenous delivered contrast bolus. Both imaging modalities provide high spatial and temporal resolution to determine regional MBF, and allow complementary measurements of cardiac function, structure, and coronary architecture. In this review, we will explore the basic principles of cardiac MR and CT perfusion imaging methods, with a special emphasis on recent emerging methods that allow for combined coronary artery and MBF measurement by CT.

Anatomical and pathophysiological classification of congenital heart disease

Congenital heart diseases (CHD) consist of defects of the cardiac architecture which interfere with the venous drainage, septation of the cardiac segments and their sequences and regular function of the valve apparatuses. In the normal heart the segments are disposed in such a way to allow deoxygenated venous blood to go to the lungs through the pulmonary artery and the oxygenated venous blood to go to the systemic organs through the aorta without mixing. Small and great circulations are in sequence, with no communication to each other. Establishing the sequence of cardiac segments is the prerequisite for planning a surgical repair. We propose a pathyphysiological classification of CHD based upon the clinical consequence of structural defects on the physiology of blood circulation. We divided cardiac anomalies in: (1) CHD with increased pulmonary blood flow (septal defects without pulmonary obstruction and with left-to-right shunt); (2) CHD with decreased pulmonary flow (septal defects with pulmonary obstruction and with right-to-left shunt); (3) CHD with obstruction to blood progression and no septal defects (no shunt); (4) CHD so severe as to be incompatible with postnatal blood circulation; and (5) CHD silent until adult age.

Dexamethasone Treatment Induces Cardiac Atrophy and Increased Proteasome Activity in MuRF1 KO mice

Cardiac hypertrophy is an independent risk factor for a number of pathologies. Muscle ring finger‐1 (MuRF1) is an E3‐ubiquitin ligase that has been implicated in the regulation of cardiac mass. The objective of this study was to investigate the effect of dexamethasone (dex) treatment (3mg/kg) on cardiac mass in 6 month old female wildtype (WT) and MuRF1 knockout (KO) mice. Cardiac architecture and proteasome activity was analyzed following 28 days of dex treatment. Dex induced significant cardiac atrophy in MuRF1KO, but not WT mice. Echocardiography measurements revealed no difference in morphology or systolic function between the two groups. Dex‐treated MuRF1KO mice had significantly higher proteasome activity in the catalytic β1 and β5 subunits. Conversely, WT mice demonstrated significantly lower activity in the same catalytic subunits. These findings demonstrate that dexamethasone causes cardiac atrophy in 6 month old MuRF1 KO mice, and this atrophy may be due in part to increases in rates of protein degradation. This finding is contrary to previous reports that states that the absence of MuRF1 attenuates cardiac atrophy due to exogenous glucocorticoid treatment. This work was supported by funds from the Muscular Dystrophy Association.

Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture

AbstractAlthough the involvement of plasminogen activator inhibitor-1 (PAI-1) in fibrotic diseases is well documented, its role in cardiac fibrosis remains controversial. The goal of this study was to determine the effect of a PAI-1 deficiency (PAI-1−/−) on the spontaneous development of cardiac fibrosis. PAI-1−/− mice developed pervasive cardiac fibrosis spontaneously with aging, and these mice displayed progressively distorted cardiac architecture and markedly reduced cardiac function. To mechanistically elucidate the role of PAI-1 in cardiac fibrosis, 12-week-old mice were chosen to study the biologic events leading to fibrosis. Although fibrosis was not observed at this early age, PAI-1−/− hearts presented with enhanced inflammation, along with increased microvascular permeability and hemorrhage. A potent fibrogenic cytokine, transforming growth factor-β (TGF-β), was markedly enhanced in PAI-1−/− heart tissue. Furthermore, the expression levels of several relevant proteases associated with tissue remodeling were significantly enhanced in PAI-1−/− hearts. These results suggest that PAI-1 is cardioprotective, and functions in maintaining normal microvasculature integrity. Microvascular leakage in PAI-1−/− hearts may provoke inflammation, and predispose these mice to cardiac fibrosis. Therefore, a PAI-1 deficiency contributes to the development of cardiac fibrosis by increasing vascular permeability, exacerbating local inflammation, and increasing extracellular matrix remodeling, an environment conducive to accelerated fibrosis.

Spontaneous Development of Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthases

The role of the nitric oxide synthase (NOS) system in cardiac architecture and function remains unknown. This point was addressed in mice that lack all 3 NOS genes. Morphological, echocardiographic, and hemodynamic analyses were performed in wild-type (WT), singly nNOS(-/-), iNOS(-/-), eNOS(-/-), and triply n/i/eNOS(-/-) mice. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS(-/-) mice and to a lesser extent in eNOS(-/-) mice, but not in nNOS(-/-) or iNOS(-/-) mice, compared with WT mice. Importantly, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A wave ratio and hemodynamic -dP/dt and Tau), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS(-/-) mice, and this was associated with enhanced LV end-diastolic pressure and increased lung wet weight, all of which are characteristics consistent with diastolic heart failure in humans. Finally, long-term oral treatment with an angiotensin II type 1 (AT(1)) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS(-/-) mice. These results provide the first direct evidence that the complete disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo through the AT(1) receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis.

Endothelin Receptor Antagonists in Diabetic Nephropathy

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and affects an estimated 150 million people worldwide. Despite optimal treatment, including glycaemic control and antihypertensive therapy (e.g., renin–angiotensin–aldosterone system [RAS] blockade), the disease progresses. A ‘late escape’ phenomenon has been described, where proteinuria reappears despite continued RAS blockade. The endothelin (ET) system is strongly involved in the pathophysiology of the disease and contributes to vasoconstriction, inflammation and proliferation. ET antagonists are promising drugs that potently slow down disease progression in animal models and have beneficial effects on cardiac structure, mitochondrial damage and microvascular architecture. However, the available ET antagonists, at least in higher doses, may also inhibit tubular endothelin receptors subtype B, which promote sodium and water excretion. The three clinical trials with avosentan and atrasentan published so far show the unique nephroprotective effects of these drugs, with a reduction of up to 45 % in albuminuria. However, fluid retention, oedema and, in higher stages of chronic kidney disease, heart failure limit their use. The reason may be that we have been using too high doses of these ET antagonists so far and they are inhibiting tubular sodium and water excretion. Thus, we will need to learn more about the role of ET and its antagonists in the tubular and collecting duct system, and on how to use these potent drugs in DN. ET antagonists are among the most promising molecules for the treatment of nephropathies. We should definitely not abandon these drugs because of the initial drawbacks in the first clinical trials.

Three-dimensional cardiac architecture determined by two-photon microtomy

Cardiac architecture is inherently three-dimensional, yet most characterizations rely on two-dimensional histological slices or dissociated cells, which remove the native geometry of the heart. We previously developed a method for labeling intact heart sections without dissociation and imaging large volumes while preserving their three-dimensional structure. We further refine this method to permit quantitative analysis of imaged sections. After data acquisition, these sections are assembled using image-processing tools, and qualitative and quantitative information is extracted. By examining the reconstructed cardiac blocks, one can observe end-to-end adjacent cardiac myocytes (cardiac strands) changing cross-sectional geometries, merging and separating from other strands. Quantitatively, representative cross-sectional areas typically used for determining hypertrophy omit the three-dimensional component; we show that taking orientation into account can significantly alter the analysis. Using fast-Fourier transform analysis, we analyze the gross organization of cardiac strands in three dimensions. By characterizing cardiac structure in three dimensions, we are able to determine that the alpha crystallin mutation leads to hypertrophy with cross-sectional area increases, but not necessarily via changes in fiber orientation distribution.

Surgical Treatment of Ischemic Heart Failure

Despite the improvements in the treatment of myocardial infarction that have translated into a decline in mortality rates, the incidence of heart failure has increased and, because of the limited number of cardiac donors, non-transplant heart surgery has developed in the past 10 years. Surgical ventricular reconstruction was launched by Dor and defined as endoventricular circular patch plasty repair. It represents a relatively novel surgical approach aiming to restore (bring back to normal) the dilated, distorted left ventricular (LV) cavity in order to improve function. The term ;surgical ventricular reconstruction/restoration' includes operative methods that reduce LV volume and restore its shape. The concept of reducing wall stress through surgical restoration of chamber size and geometry remains the guiding principle behind this innovative technique. Results from different Institutions are uniform and show an improvement in cardiac and clinical status and in survival. The present review will approach the rationale to re-shape the heart on the basis of pathophysiology and cardiac architecture, and will describe the efficacy of the Dor procedure in ischemic dilated cardiomyopathy, as well as some technical aspects and patient selection pathway.

Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones, secretions of which are markedly upregulated during cardiac failure, making their plasma levels clinically useful diagnostic markers. ANP and BNP exert potent diuretic, natriuretic and vasorelaxant effects, which are mediated via their common receptor, guanylyl cyclase (GC)-A (also called natriuretic peptide receptor (NPR)-A). Mice deficient for GC-A are mildly hypertensive and show marked cardiac hypertrophy and fibrosis that is disproportionately severe, given their modestly higher blood pressure. Indeed, the cardiac hypertrophy seen in these mice is enhanced in a blood pressure-independent manner and is suppressed by cardiomyocyte-specific overexpression of GC-A. These results suggest that the actions of a local cardiac ANP/BNP-GC-A system are essential for maintenance of normal cardiac architecture. In addition, GC-A was shown to exert its cardioprotective effects by inhibiting angiotensin II-induced hypertrophic signaling, and recent evidence suggests that regulator of G protein signaling (RGS) subtype 4 is involved in the GC-A-mediated inhibition of Gαq-coupled hypertrophic signal transduction. Furthermore, several different groups have reported that functional mutations in the promoter region of the human GC-A gene are associated with essential hypertension and ventricular hypertrophy. These findings suggest that endogenous GC-A protects the heart from pathological hypertrophic stimuli, and that humans who express only low levels of GC-A are genetically predisposed to cardiac remodeling and hypertension.

Shunting and pressure separation in reptiles inferred from cardiac architecture

Shunting and pressure separation in reptiles inferred from cardiac architecture

Surgical Restoration of the Postinfarction Dilated Ventricle

Surgical restoration of the failing heart is related to rebuilding cardiac architecture and linked to: (a) understanding that the structure of the failing dilated heart involves changing the normal elliptic shape toward a dilated spherical form; (b) recognizing the anatomic fiber orientation framework and its functional implications; (c) establishing imaging measurement guidelines to determine indications for surgical intervention that focus upon volume and remote muscle evaluation rather than ejection fraction; and (d) summarizing left ventricular restoration results whereby rebuilding normal elliptic configuration improves function, reduces ventricular arrhythmias, alleviates mechanical dyssynchrony, and causes progressive improvement that extends long-term prognosis.

Quest for Diastolic Prognostic Indicators of Clinical Outcome After Acute Myocardial Infarction

Immediately after acute infarction, the region of the myocardium ceases to contract, and over the next 72 hours, the infarct zone stretches and thins, a process known as infarct expansion. This regional left ventricular wall thinning and failure to contract perturb the normally uniform distribution of the stress/strain relationship that preserves cardiac architecture and function. Simultaneous with these early biomechanical changes, myocyte necrosis releases a number of cytokines that, together with the local increase in the regional myocardial deformation, cause stretch activation of a portfolio of matrix metalloproteinases that initiate myocardial repair. Article p 2591 The stability of myocardial repair after acute myocardial infarction is determined by the balance between the distending forces from ventricular dilatation resulting from infarct expansion and the restraining forces from deposition of a viscoelastic collagen scaffold by the extracellular matrix that increases the tensile strength of the scar. The dynamic equilibrium between collagen degradation and collagen deposition is modulated by a number of activated cytokines and neurohormones that normally result in buttressing the infarct and adjacent border zones, preventing progressive remodeling to heart failure. Changes in the composition of the myocardium in terms of increased collagen content during and after repair of the infarct zone in forming a fibrous tissue scar alter the material properties of the myocardium after myocardial infarction and confer on the heart increased myocardial and chamber stiffness. These alterations in left ventricular composition, architecture, and chamber/myocardial stiffness affect left ventricular filling dynamics, the rate of detachment of cross-linking, and sequestration of cytosolic calcium by the sarcoplasmic reticulum, all of which affect diastolic function as much as systolic function. However, most studies of the predictors of clinical outcome after myocardial infarction have focused almost exclusively on ejection-phase indexes of systolic contraction. Factors shown to be powerful predictors of clinical outcome after myocardial …

Functional angiotensin‐converting enzyme 2 is expressed in human cardiac myofibroblasts

The renin-angiotensin system (RAS), in particular angiotensin II, plays an important role in cardiac remodelling. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key players in the RAS and act antagonistically to regulate the levels of angiotensin II. In this study, we reveal the functional expression of ACE2 in human cardiac myofibroblasts, cells that are essential to the maintenance of normal cardiac architecture and also play a key role in myocardial remodelling. The observed reciprocal expression of ACE and ACE2 in these cells may reflect the possible opposing activity of these two enzymes. In this study, we demonstrate the presence of ACE2 as an ectoenzyme and reveal that ACE2 undergoes phorbol-12-myristate-13-acetate-inducible ectodomain shedding from the membrane. When cells were exposed to a number of pathophysiological stimuli, modulation of ACE2 levels was not detected. Importantly, whilst we found ACE2 to be expressed constitutively in cardiac myofibroblasts there were no detectable levels in either vascular smooth muscle cells or vascular endothelium, indicating that ACE2 expression is not ubiquitous. In paraffin sections of atrial appendage tissue, we observed a distinct staining pattern for ACE2 which appeared different from that of ACE. In conclusion, this study is the first to report co-expression of ACE and ACE2 in human cardiac myofibroblasts and may therefore present a model primary system for study of the comparative cell biology of ACE2 and ACE and their potentially opposing roles in myocardial remodelling.