During echocardiographic examination, respiration induces cyclic physiological changes of intracardiac haemodynamics, causing normal variations of the right and left ventricle Doppler inflows and outflows and physiological variation of extracardiac flows. The respiration related hemodynamic variation in intra and extracardiac flows may be utilized in the echocardiography laboratory to aid diagnosis in different pathological states. Nevertheless, physiologic respiratory phases can cause excessive translational motion of cardiac structures, lowering 2D image quality and interfering with optimal Doppler interrogation of flows or tissue motion.This review focuses on the impact of normal respiratory cycle and provocative respiratory maneuvers in echocardiographic examination, both in physiological and pathological states, emphasizing their applications in specific clinical situations. Respiration induces cyclic physiological modification of intracardiac haemodynamics. Changes are related to variations in intrathoracic and intraabdominal pressure, systemic and pulmonary venous return, intrapericardial pressure, pericardial constraint and interdependence between the four cardiac chambers. With inspiration intrathoracic and intrapericardial pressures decrease. This results in augmented right ventricular filling and stroke volume and, as the total pericardial space is limited, a compensatory decrease in left ventricular stroke volume occurs in early inspiration. With expiration, intrathoracic and intrapericardial pressures increase, resulting in mild decrease in right ventricular diastolic filling and a subsequent increase in left ventricular filling.Because of the constraining effect of the pericardium on the combined volume of the four cardiac chambers, respiratory variation in intrapericardial pressure results in reciprocal variation in the filling of both ventricles .With inspiration the anteroposterior diameter of the chest increases, and the lungs inflate and expand particularly anteriorly, partly filling the space between the heart and the thoracic cage. Inspiratory movements do not only decrease the amount of cardiac tissues that lies close to the sternum through anterior pulmonary expansion, but also produce a posterior displacement and rotation of the heart relative to a fixed echo beam .Expiration will give a better parasternal and often apical access to the heart by lungs deflation  and diastolic (D) flow velocities as well as retrograde A velocity compared to apnea. Figure .The normal forward biphasic flow velocity pattern in the superior vena cava (SVC) with systolic flow velocity greater than diastolic flow velocity, shows inspiratory changes similar to those of hepatic vein flow.Respiratory variations are minimal for pulmonary vein flow Figure Diaphragmatic traction associated with respiration changes the position of intracardiac structures in relation to a fixed Doppler sample volume causing errors in velocities measurement.The Doppler sound beam should be oriented as parallel as possible to the flow, guided both by the 2D image (sometimes assisted by color flow imaging). Small (<20 degrees) deviations in angle produce mild (<10%) errors in velocity measurements. Although these errors may be acceptable for low-velocity flows, when Doppler is used to derive pressure gradients even a small error in velocity measurement can lead to significant underestimation of the gradient because of the quadratic relation between velocity and pressure gradient. The effects of respiration can be minimized by taking measurements during short periods of apnea or by averaging multiple consecutive beats ,8.The phase of respiration affects Doppler Tissue Imaging (DTI) recordings in the same manner because the shift in heart position during respiration over a fixed Doppler sample volume leads to inaccurate recording of the annular velocities Figure .Whenever possible, the echocardiographer should obtain annular DTI recordings during end-expiratory apnea Figure . Once thEvaluation of the inferior vena cava (IVC) from the subcostal view is part of the routine TTE examination. The diameter of the IVC decreases in response to inspiration with minimal size observed at end inspiration when the negative intrathoracic pressure leads to an increase in RV filling from the systemic veins. IVC size is significantly influenced by patient position, being largest in the right lateral position, intermediate in the supine position, and smallest in the left lateral position . The dia• The normal IVC diameter is less than 1.7 cm and there is a 50% decrease in the diameter when the RA pressure is normal (0–5 mm Hg).• A dilated IVC (>1.7 cm) with normal inspiratory collapse (>50%) is suggestive of a mildly elevated RA pressure (6–10 mm Hg).• When the inspiratory collapse is less than 50%, the RA pressure is usually between 10 and 15 mm Hg.• Finally, a dilated IVC without any collapse suggests a markedly increased RA pressure of greater than 15 mm Hg. Figure .A small IVC  with spontaneous collapse is often seen in the presence of intravascular volume depletion .In a recent paper, Brennan et al evaluated the IVC diameter in patients undergoing right heart catheterization . The mea(1) High collapsibility with a small or normal-sized IVC; RAP is very likely low (<5 mm Hg).(2) High collapsibility with a large IVC or normal collapsibility with a small/normal-sized IVC; RAP is probably between 0 and 10 mm Hg(3) Normal collapsibility with large IVC; RAP is 10 to 15 mm Hg(4) Low collapsibility with a large IVC; RAP is clearly high (10–20 mm Hg)(5) RAP in patients with low collapsibility and a normal-sized or small IVC should be interpreted as indeterminate.There are several additional conditions to be considered when evaluating the IVC:• Athletes have been shown to have dilated IVCs with normal collapsibility index• In mechanically ventilated patients, the relationship between IVC and RAP is controversial; it was shown that a dilated IVC did not always indicate a high RA pressure Nonetheless a small IVC (< 1.2 cm) had a 100% specificity (with a low sensitivity) for a RA pressure of less than 10 mm Hg. It was also suggested that the IVC diameter measured at end expiration and end diastole using M-mode echocardiography correlates better with RA pressure than IVC diameter at end-expiration without ECG synchronization .In patients with chronic obstructive pulmonary disease (COPD) pulmonary hypertension (PH) is sometimes difficult to assess by direct evaluation using the tricuspid regurgitant Doppler velocity because of emphysema or mediastinal deviation. An alternative method of respiration-aided evaluation of PH was proposed by Kunichika et al . AuthorsTransmitral Doppler flow parameters are widely used in the assessment of LV diastolic function. It is well known that with spontaneous respiration small changes <15%) in transmitral peak flow velocities occur in healthy subjects. While some authors found no alteration in the ratio of early-to-late peak flow velocity (E/A) % in tran.The potential effects of spontaneous respiration on mitral inflow Doppler patterns in patients with abnormal LV diastolic function are poorly understood. Tsai et al.  observedIn diseased ventricles, progressive shortening of the transmitral DT and increasing E/A ratio can be seen with decreasing ventricular compliance and increasing left atrial pressure. Impaired relaxation is frequently masked by elevated filling pressures resulting in a pseudonormal flow pattern (E/A ratio >1). The Valsalva maneuver has been found to effectively unload the heart and unmask an impaired relaxation pattern and high filling pressures in patients with a baseline pseudonormal flow pattern. This maneuver is accomplished first by cessation of breathing at any point in the respiratory cycle when assessment of mitral inflow is optimized. Next, the participant exerts a firm contraction of the abdominal muscles to force air against the closed glottis for approximately 10 seconds thereby increasing the intrathoracic pressure. In order to be properly performed, the Valsalva maneuver should be standardized. This can be done by attaching a mouthpiece (e.g. the tube of a syringe from which the plunger has been detached) to a sphygmomanometer and asking the patient to blow into it in order to raise the column of Hg to 40 mm and keep it stable at this value for 10 seconds . This reChanges in transmitral E/A ratio during the Valsalva maneuver across different stages of diastolic dysfunction were recently described by Reagan et al .Because the E/A ratio increases as filling pressures rise it is generally assumed that an E/A ratio <1 (impaired relaxation pattern) indicates lower or even normal filling pressures when compared with patients who have a pseudonormal or restrictive filling pattern. However, Schwammenthal et al demonstrated that patients with an E/A ratio of <1 can nonetheless have severely elevated filling pressures. In these patients LV relaxation is so severely impaired that E/A ratio remains <1 despite increased filling pressures. The standardized Valsalva maneuver can unmask the presence of elevated filling pressures in patients with a baseline impaired relaxation pattern. The A wave will increase during the maneuver in patients with elevated filling pressures in proportion to the level of LV end-diastolic pressure, and independent of the baseline transmitral flow pattern .Figure The increased pericardial pressure in cardiac tamponade produces reciprocal respiration-related changes in right and left ventricular volumes, diastolic filling, and systolic emptying that can be documented by echocardiography. The normal effects of respiration are accentuated such that venous return and right-sided filling occur during inspiration as intrathoracic pressures fall, providing a pressure gradient from the systemic veins to the RA. Because the total intrapericardial volume is fixed by the pressurized effusion, this increased inspiratory RV filling causes the interventricular septum to shift to the left, exaggerating the normal decrease in LV filling volume and, hence, stroke volume (ventricular interdependence). Thus, in tamponade, left heart filling occurs preferentially during expiration when there is less filling of the right heart. The small normal respiratory variation in left ventricular (LV) stroke volume and systolic arterial pressure <10 mm Hg) is markedly accentuated in cardiac tamponade, resulting in the clinical finding of "paradoxical pulse" 0 mm Hg i-24.Echocardiography is particularly useful in demonstrating the exaggerated phasic variation in cardiac volumes and flows caused by tamponade . The diaRespiratory variation in tricuspid and pulmonary flow is more dramatic than mitral and aortic flow, but there is progressive impairment in all intracardiac flows as the degree of tamponade worsens: with inspiration, the RV early diastolic filling is augmented (>25%), while LV diastolic filling diminishes >15%). The flow velocity integral in the pulmonary artery increases with inspiration, while the aortic flow velocity integral decreases (>10%) [5%. The fThe hepatic vein flow pattern may also reflect the exaggerated respiratory phase dependency of right ventricular filling. The loss of forward flow in the hepatic veins during the expiration phase of the respiratory cycle with flow out of the hepatic veins confined to the early inspiratory phase can be observed in patients with hemodynamically significant pericardial effusion . SuperioIn constrictive pericarditis, the rigid pericardium impedes the transmission of intrathoracic pressures to the cardiac chambers. During inspiration there is a lower driving force from the lungs into the left side of the heart and the LV becomes underfilled. The constricting pericardium also results in an increase interventricular interaction, so that with LV volume decrease, there is a corresponding increase in right ventricular volume  see AddIn Doppler echocardiographic studies the dissociation of intrathoracic and intracardiac pressures is manifested by an inspiratory increase in peak tricuspid flow velocity and a simultaneous decrease in mitral flow velocity, with opposite changes occurring in expiration .• PW Doppler mitral inflow: high E velocity, E/A ratio > 2, short E wave deceleration time (EdT < 160 ms); inspiration: decrease E velocity >25%, prolonged IVRT >25%; expiration: opposite changes Figure • PW Doppler tricuspid inflow: E>A; inspiration: increased tricuspid E velocity >35%, characteristic phenomenon increased TR velocity Figure • PW Doppler recordings of hepatic vein flow: inspiration-minimally increased S and D; expiration: decreased diastolic flow/exaggerated atrial reversal waves Figure • PW Doppler recordings of pulmonary vein flow: S/D ratio = 1, inspiration: decreased PV S and D waves, expiration: opposite changes• SVC Doppler usually shows a diastolic dominant pattern, minimal respiratory variation as right atrial pressure is constantly elevated throughout the respiratory cycle by the thickened, constraining pericardium• Inspiration: aortic velocity decreases (-14 ± 5%), pulmonary artery velocity increases (16 ± 4%)• Dilated IVC with reduced inspiratory change in diameter• Respiratory changes in the proximal aortic waveform in constrictive pericarditis, similar to those described in the LV outflow tract and transmitral pattern, are reported by some authors : an inspThere are some clinical and hemodynamic situations that cause difficulties in revealing the significant respiratory Doppler findings for constrictive pericarditis as follows:notably elevated left atrial pressure, respiratory variation of the Doppler inflows may not be present unless preload is reduced by head-up tilt or diuretics [• In patients with iuretics Not all patients with surgically proven constriction actually have increased respiratory variation of Doppler inflows [•  inflows .atrial fibrillation some authors [• In patients with  authors  reportedafter pericardiectomy• The same pattern of constriction, with respiratory variations, can persist for variables time periods chronic obstructive pulmonary disease (COPD) [• Patients with e (COPD)  without Respiratory maneuvers are very useful in echocardiographical differential diagnosis constrictive pericarditis (CP) – RCM (restrictive cardiomyopathy) as follows  because ventricular filling is limited mainly by a noncompliant restrictive myocardium rather than a constrictive pericardium. In addition, these patients usually have markedly increased left atrial and pulmonary venous pressure. Thus, the normal inspiratory intrathoracic pressure decline may cause minimal change in pulmonary venous and left atrial pressure.cardiac tamponade, constrictive pericarditis, chronic obstructive pulmonary disease, but also by acute right ventricular dilatation due to right ventricular infarction or pulmonary embolism. Most of these conditions can be distinguished by clinical and morphological echocardiographic features  can be reliably detected with contrast echocardiography, using agitated saline; the transthoracic and transesophageal echocardiography evaluation for detecting a patent foramen ovale is performed during normal respiration and during Valsalva maneuver During Valsalva, atrial shunting from right to left will begin during the release phase (phase III) . The ValThe right-to-left shunt of a large atrial septal defect may be nearly continuous, whereas for smaller atrial septal defects the appearance of contrast in the left atrium may be phasic, coordinated with the respiratory cycle; during inspiration, right heart filling increases, thus increasing the flow of contrast into the right atrium.In patients with obstructive hypertrophic cardiomyopathy the obstruction of the LV outflow tract is dynamic and may be mild or nonexistent at rest. Echocardiography during Valsalva maneuver can unmask latent gradients in patients without resting obstruction and reveal the basis for drug treatment choices. During the strain phase of Valsalva maneuver, due to the decrease in preload, end-diastolic left ventricular volume and afterload, SAM occurs earlier in systole, mitral-septal contact lasts longer and left ventricular outflow tract gradient increases Figure .Due to left ventricular volume decrease during Valsalva maneuver in patients with mitral valve prolapse mitral regurgitation starts earlier in systole and severity of mitral regurgitation increases.The Mûller maneuver, the opposite of Valsalva, less often used in echo examinations, is performed by forcibly inspiring while the nose is held closed and the mouth is sealed for about 10 seconds. Because the maneuver exaggerates inspiratory effort, right-sided filling is augmented and can be use for the augmentation of tricuspid regurgitation.• In the absence of normal sinus rhythm, respiratory variation of Doppler flow cannot be assessed. An irregular heart rhythm does not allow a meaningful interpretation of the influence of respiration on transvalvular Doppler flow.• The Valsalva maneuver should only be performed in a standardized manner. Lack of standardization of the Valsalva maneuver can limit its feasibility and, more importantly, can lead to wrong conclusions.• The use of Valsalva maneuver is limited in certain conditions: lack of patient' cooperation; patient's inability to adequately increase intrathoracic pressure because of medical illness, recent operation, sedation (eg during TEE).• The decrease in image quality sometimes encountered during Valsalva maneuver or with normal respiration may interfere with the interpretation of the findings. However, appropriate training and regular use of respiratory maneuvers help in this regard.Using normal respiratory phases and provocative respiratory maneuvers  can be very useful in characterizing normal cardiac function parameters as well as various cardiac disorders Table . The extThe authors declare that they have no competing interests.CG conceived of the review, participated in its coordination and revised the final draft of the manuscript. CCB revised the literature, prepared the final draft of the manuscript and provided echocardiographic illustrations. MI revised the literature and prepared the first draft of the manuscript. AC revised the manuscript critically for important intellectual content. BAP participated in the coordination of this review and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.Changes in the quality of the echocardiographic image with inspiration. Transthoracic parasternal long axis view of the left ventricle recorded with normal respiration revealing a decrease in the quality of the echocardiographic image with inspiration.Click here for fileImprovement in the quality of the echocardiographic image recorded during held end expiration. Transthoracic parasternal long axis view of the left ventricle recorded during held end expiration showing a significant improvement in the quality of the echocardiographic image.Click here for fileInfluence of pulmonary interference on echocardiographic visualization of cardiac structures during normal respiration. Transthoracic apical 4 chamber view recorded during normal respiration. During inspiration pulmonary interference does not allow the visualization of cardiac structures.Click here for fileInfluence of expiration on echocardiographic visualization of cardiac structures. Transthoracic apical 4 chamber view. Expiration allows apical access to the heart by lung deflation.Click here for fileInfluence of inspiration on echocardiographic image in subcostal view. Subcostal 4 chamber view. Inspiration brings the diaphragm down, improving imaging of the heart.Click here for fileExcessive translational motion of the heart with normal respiration. Transthoracic short axis view recorded during normal respiration. The heart moves medially with inspiration.Click here for fileImage acquisition during suspended respiration (held end-expiration) in a patient with excessive translational motion of the heart with normal respiration. Transthoracic short axis view. Excessive translational motion can be avoided by acquiring images during held end-expiration.Click here for fileLack of variation of the inferior vena cava diameter during deep inspiration in a patient with dilated cardiomyopathy and severe pulmonary hypertension. The subcostal view adjusted to demonstrate the long axis of the inferior vena cava (IVC) in a patient with dilated cardiomyopathy and severe pulmonary hypertension. There is no inspiratory variation of the IVC diameter during deep inspiration.Click here for fileLack of variation of the inferior vena cava diameter during brief sniff in a patient with dilated cardiomyopathy and severe pulmonary hypertension. Evaluation of the inferior vena cava (IVC) from the subcostal view during brief sniff in a patient with dilated cardiomyopathy and severe pulmonary hypertension demonstrates no variation of the IVC diameter.Click here for filePhasic variation in cardiac volumes visualized in transthoracic basal short axis view caused by cardiac tamponade. Transthoracic basal short axis view in a patient with cardiac tamponade demonstrates diastolic collapse of the free walls of the right atrium and right ventricle.Click here for filePhasic variation in cardiac volumes caused by cardiac tamponade, visualized in transthoracic apical 4 chamber view. The intermittent collapse of the free walls of the right atrium and right ventricle visualized in the transthoracic apical 4 chamber view in a patient with cardiac tamponade.Click here for fileIncreased interventricular interaction in a patient with constrictive pericarditis. Transthoracic apical 4 chamber view in a patient with constrictive pericarditis reveals the increased interventricular interaction (with left ventricular volume decrease there is a corresponding increase in right ventricular volume).Click here for file


In patients with Duchenne Muscular Dystrophy (DMD), the absent or diminished dystrophin leads to progressive skeletal muscle and heart failure. We evaluated the role of myocardial inflammation as a precipitating factor in the development of heart failure in DMD.20 DMD patients (aged 15-18 yrs) and 20 age-matched healthy volunteers were studied and followed-up for 2 years. Evaluation of myocarditis with cardiovascular magnetic resonance imaging (CMR) was performed using STIR T2-weighted (T2W), T1-weighted (T1W) before and after contrast media and late enhanced images (LGE). Left ventricular volumes and ejection fraction were also calculated. Myocardial biopsy was performed in patients with positive CMR and immunohistologic and polymerase chain reaction (PCR) analysis was employed.In DMD patients, left ventricular end-diastolic volume (LVEDV) was not different compared to controls. Left ventricular end-systolic volume (LVESV) was higher  and left ventricular ejection fraction (LVEF) was lower . T2 heart/skeletal muscle ratio and early T1 ratio values in DMD patients presented no difference compared to controls. LGE areas were identified in six DMD patients. In four of them with CMR evidence of myocarditis, myocardial biopsy was performed. Active myocarditis was identified in one and healing myocarditis in three using immunohistology. All six patients with CMR evidence of myocarditis had a rapid deterioration of left ventricular function during the next year.DMD patients with myocardial inflammation documented by CMR had a rigorous progression to heart failure. Duchenne Muscular Dystrophy (DMD) is a myopathy characterized by a defect in the p21 band of the X chromosome that is responsible for dystrophin, a protein located on the inner surface of the sarcolemma. In affected individuals, the absent or diminished dystrophin leads to progressive skeletal muscle and heart failure .Cardiovascular magnetic resonance imaging (CMR) has the unique ability to detect coronary anatomy, function and viability in one examination . The useOur aim was to evaluate a population of DMD patients, suspected for myocarditis, using CMR and myocardial biopsy, in order to examine the hypothesis that myocardial inflammation could be a precipitating factor for heart failure in these patients.In this prospective study, twenty consecutive DMD patients (aged 15-18 years) selected from Pediatric Neuromuscular clinics due to a recent onset (last six months) of atypical chest discomfort or fatigue without new ECG changes, were evaluated in our tertiary cardiac center and followed-up for 2 years. All patients were male and presented with proximal muscle weakness before age of 5 years, and increased serum creatine kinase. They were under prophylactic treatment with perindopril since the age of 10 yrs. The diagnosis of DMD was initially based on the characteristic clinical history and neuromuscular findings and was confirmed in all of them by DNA testing. The DMD patients had lost ambulation between 7 and 11 years; they were wheelchair-bound and had moderate to severe scoliosis. All of them had evidence of right ventricular hypertrophy and non-specific ST changes in the ECG and in the Holter monitor examination presented evidence of supraventricular ectopy. Their results were compared with those of 20 age and sex-matched healthy volunteers. In DMD patients with CMR positive for myocardial inflammation, a myocardial biopsy was also considered, as part of standard evaluation of suspected myocarditis.All subjects (or their parents) gave informed consent. The study was approved by the hospital's ethics committee.Cardiovascular magnetic resonance examination was performed in a 1.5 T Philips Intera system using STIR T2-weighted (T2-W), T1-weighted (T1-W) before and after contrast media injection and late enhanced images (LGE). ECG-triggered, STIR T2-W multislice spin-echo sequence was performed in axial orientation and the signal ratio measured from the region of interest covering the left ventricular myocardium as well as within a skeletal muscle in the same slice. T2-W, an inherent indicator of tissue water content, is increased in inflammation or necrosis due to the development of edema, such as during myocardial infarction or myocarditis.ECG-triggered T1-W multislice spin-echo images were also obtained in axial orientation with identical parameters before and after an intravenous bolus of 0.1 mmol/kg Gd-DTPA. Measurements after Gd-DTPA were started within 1 minute of injection (early T1) in the same area as in T2-W. The extracellular T1-enhancing contrast agent was used to enhance the detection of pathology on CMR Gd-DTPA. Higher levels of early myocardial enhancement after gadolinium are most likely due to increased cell membrane permeability . This prImmediately after the second set of T1-W images, 0.1 mmol/kg Gd-DTPA was given again and epicardial late gadolinium-enhanced areas (LGE) were taken 15 min later, using an a 3D-T1-TFE sequence, preconditioned with a 180 degrees inversion pulse . Images were analyzed according to previously described protocols [For each subject, localizing scans were obtained to define the long (2-chamber) axis of the left ventricle. A mid ventricular short axis view was then prescribed, and used to plan a 4-chamber view. The short axis orientation was defined accurately, perpendicular to both the 2- and 4-chamber views. To cover the entire left ventricle, 10 contiguous (gap = 0 mm) short axis slices were acquired in each study. The imaging sequence was a 2D, multi-phase , steady-state free-precession (SSFP) sequence  characterized by the application of balanced gradients in all directions.After written informed consent, 10 endomyocardial specimens (EMBs) were obtained from the right side of the ventricular septum of each patient with a flexible bioptome  via the femoral vein approach. Four myocardial specimens were used for the histological evaluation according to the Dallas criteria and immunohistochemistry respectively, whereas the remaining 6 were subjected to DNA and RNA extraction of viral genomes.EMBs were stained with hematoxylin-eosin, Masson's trichrome as well as Giemsa stain and examined by light microscopy . For immThe detection of >14 infiltrating leukocytes/mm2 in the presence of myocyte damage and or fibrosis in addition to enhanced HLA class II expression in professional antigen-presenting immune cells and endothelium was used for the diagnosis of active myocarditis. Healing myocarditis was considered if the inflammation was less extensive (<14 leukocytes/mm2), whereas healed myocarditis was characterized by multifocal fibrosis or scarring without inflammation /reverse transcriptase (RT)-PCR was performed for the detection of EVs (including Coxsackieviruses and Echoviruses), ADVs, Parvovirus B19 (PVB19), Human Cytomegalovirus, Epstein-Barr-virus, Herpes virus 1-6, Chlamydia pneumoniae and trachomatis. The quality (purity) and quantity of the extracted nucleic acids  was evaluated on a Nanodrop 2000c spectrophotometer (ThermoScientific). As a control for the successful extraction of RNAs, as well as for the presence of PCR inhibitors a Reverse Transcription Real Time PCR assay was designed with primer/probe sequences from the G-6PDH (glucose-6-phosphate dehydrogenase) or b2-microglobulin or human acidic ribosomal protein cDNAs (data not shown). For the verification of the DNA extraction a conventional PCR assay was designed with specific primers for the human b-globin gene  -12.DNA was extracted with the use of the DNeasy tissue Kit  according to the manufacturer's instructions and was stored at -20°C for further processing.Total RNA was extracted with the use of RNeasy Mini Kit  according to the manufacturer's instructions. Total RNA was collected in 40 μl of RNase free water.Continuous data were expressed as mean ± SD. Statistical analysis was performed using Mann-Whitney U-test. A p-value of < 0.05 was considered for statistical significance.In DMD patients, left ventricular end-diastolic volume (LVEDV) was not different compared to controls . However, left ventricular end-systolic volume (LVESV) was higher  and left ventricular ejection fraction (LVEF) was lower compared to controls . T2 heart/skeletal muscle ratio and early T1 ratio values in DMD patients did not differ compared to controls .However, in one patient, although left ventricular indexes were within normal range, the T2 ratio and early T1 values were increased compared to controls (2.3 and 12 respectively) and a intramural late gadolinium enhanced area (LGE) in the intraventricular septum of the left ventricle was also identified  Figure , while ePolymerase chain reaction (PCR) revealed Human Cytomegalovirus (CMV) in the patient with active myocarditis, while Parvovirus B19 and Coxsackie B virus were identified in the remaining three patients with postero-lateral LGE areas. During the next year and in a time period between 6-12 months, all 6 DMD patients with CMR evidence of myocarditis (LGE+) developed left ventricular dilatation, rapid deterioration of left ventricular ejection fraction and arrhythmias including bigeminy and/or ventricular tachycardia. In the second year of follow-up, two of them died due to ventricular tachycardia and the other 4 were in end-stage heart failure. It is also important to mention that the DMD patients without evidence of myocarditis (LGE-) remained stable and did not develop any deterioration of heart function during the next 2 years. A Kaplan-Meier graph of the probability of heart failure between LGE+ and LGE- DMD patients is presented in figure In this study, the evaluation of twenty DMD patients by CMR revealed the presence of myocardial fibrosis in 6/20. DMD patients suspected for myocarditis were oligo-symptomatic and their left ventricular indexes, although within normal range, presented significantly lower than those of age - matched controls. In DMD subjects with positive CMR findings, endomyocardial biopsy assessed the presence of active and healing myocarditis and PCR evaluation documented the presence of CMV, Coxsackie and Parvo-B19 in some of them. During the next 1- 2 years, DMD patients with evidence of myocardial inflammation had a rapid progression to heart failure and death, in contrast to the DMD patients without evidence of myocarditis by CMR, who remained stable.This is an initial report documenting the presence of myocarditis in a population of oligo-symptomatic DMD patients, using CMR and verified by myocardial biopsy. Our group has already described a case of a DMD patient with sudden clinical deterioration and clinical suspicion of myocarditis (this patient is not included in the present study), initially diagnosed by CMR and then verified by myocardial biopsy . CMR hasThe cardiac involvement in DMD, which is characterized by cardiac muscle degeneration with fibrous tissue replacement and fatty infiltration, typically occurs late in the course of the disease. It is estimated that about 75% of DMD patients die due to respiratory failure and about 20% of them due to heart failure . These fIn an effort to detect early myocardial disease, previous studies used different non-invasive techniques, including 201-Thallium scintigraphy . In a grOur findings were in agreement with previous studies, which also assessed the presence of epicardial myocardial fibrosis in DMD patients using CMR ,7 and otAlthough it is known that the absence or decrease of dystrophin leads to progressive skeletal muscle and heart failure , recentlThe small number of examined patients and the small number of myocardial biopsies taken from intraventricular septum and not from the gadolinium late enhanced areas are the major limitations of this study. Additionally, our patients were selected due to recent onset of possible cardiac involvement from Pediatric Neuromuscular Hospitals and do not reflect the real incidence of myocarditis in the DMD population.In conclusion, in DMD, which is traditionally considered as a degenerative muscular disease, the myocardial inflammation documented by CMR and myocardial biopsy was a precipitating factor for heart failure. DMD patients with myocarditis had rapid LV deterioration in contrary to those without, who remained stable during the 2 years of follow-up. However, further studies are needed to evaluate the true incidence of myocarditis and the importance of these findings in the pathophysiology of development of heart failure in DMD patients.The authors declare that they have no competing interests.SM conceived of the study, and participated in its design and coordination, in the imaging studies and helped to draft the manuscript. AP participated as a pediatric neurologist who followed these patients. KS ED SP performed the cardiac biopsiesPC carried out the PCR studies. GP, EK, DG and GK participated as cardiologists who followed these patients. LK carried out the pathology studies. AM and EP carried out the imaging studies. VM participated in the design of the study and performed the statistical analysis. DVC participated in the design and coordination of the study.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/10/33/prepub


Background and Objectives. We evaluated and compared the influence of treatment for atrial septal defect (ASD), patent ductus arteriosus (PDA), and coarctation of the aorta (CoA) on serum levels of N-terminal proatriopeptide and N-terminal probrain natriuretic peptide. Correlations between peptide levels and echocardiographic measurements were calculated. Patients and Methods. Peptide levels were measured and echocardiography performed before and 6–12 months after treatment in 21 children with ASD, 25 with PDA, 15 with CoA, and 76 control children. Results. ANPN levels were higher than in controls at baseline in all patient groups, and NT-proBNP in patients with ASD and PDA. Both peptide levels were elevated 6 months after treatment and decreased thereafter. Peptide levels were higher in patients with volume than pressure overload. They correlated with echocardiographic measurements. At the 6-month follow-up, dimensions of the originally overloaded ventricle had normalized only in patients with PDA. Conclusions. After intervention, peptide levels decrease but normalization takes over 6 months. The type of correlation between peptide levels and echocardiography varies according to the loading condition. Measurement of peptide levels can be used for monitoring the course of a patient's heart disease. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide, and dendroaspis natriuretic peptide form the natriuretic peptide system. They have an important role in regulation of fluid homeostasis, blood pressure/vascular tone, and cardiomyocyte growth. This system functions to retard the progression of heart failure, opposite to the effect of neurohumoral systems like the renin-angiotensin-aldosterone system and the sympathetic nervous system , 2.ANP is produced primarily in the atrial myocyte and in smaller amounts in ventricular myocytes. It appears in fetal ventricular tissue and in hypertrophied ventricles. It is stored as a prohormone in atrial granules and released in response to wall stress. In the presence of heart disease, ANP gene expression is upregulated in ventricular myocytes , 3. BNP Normal levels of ANP and BNP and their inactive N-terminal fragment have been investigated using different methods –11. For Atrial septal defect (ASD) predisposes the patient to volume overload of the right side of the heart, increased pulmonary vascular resistance, and atrial arrhythmias , 18. TheThe timing of treatment for congenital heart defect is based on the hemodynamic and anatomic situation, with consideration of myocardial cell adaptation and chamber remodeling. Therefore, it is important to have multiple methods available for follow-up. The combination of new imaging modalities and measurement of serum levels of natriuretic peptides may allow us to improve evaluation of cardiac function and timing of interventions.N-terminal proatriopeptide (ANPN) and N-terminal probrain natriuretic peptide (NT-proBNP) may have different regulation of gene expression depending on the form and localization of the stress exerted on the heart. Therefore, treatment for different types of loading condition may cause different types of changes in levels of these peptides. The purpose of this study was to evaluate the influence of treatment for different loading conditions on serum levels of ANPN and NT-proBNP. We correlated peptide levels to two-dimensional (2D) and three -dimensional (3D) echocardiographic findings in these conditions.This prospective follow-up study was carried out at the Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland, between February 2003 and February 2006. All parents agreed to have their children participate in this clinical trial approved by the hospital ethics committee and gave their written informed consent.The study groups consisted of 61 patients undergoing percutaneous or surgical treatment for ASD, PDA, or CoA. Twenty-one patients had an ASD, 25 a PDA, and 15 a CoA. The control group comprised 76 healthy voluntary children of whom 64 were 6 months or older. Demographics of children with ASD, PDA, CoA, and controls are shown in All patients and controls underwent clinical cardiovascular examination and blood test sampling for measurement of natriuretic peptides at the time of echocardiographic examinations. All patients were examined just prior to the intervention and 6 months later. The children with ASD and CoA were also examined 12 months after intervention. Control children were examined once. They were asymptomatic and showed no abnormalities in clinical examination, ECG, or echocardiography. Serum samples were frozen at −20°C. Serum concentrations of ANPN were measured by immunofluorometric assay. The reagents were manufactured by Medix Biochemica  and the instruments by Delfia Research Fluorometer . Serum concentrations of NT-proBNP were measured by the electrochemiluminometric method. The reagent kit was manufactured by Roche , and the samples were analyzed at Limbach Laboratory .We used the Acuson Sequoia C256 echocardiography system  for 2D imaging and for Doppler and M-mode measurements. Three-dimensional echocardiography was performed with TomTec computer software . Two-dimensional echocardiographic examinations were carried out by two observers (A. Eerola and E. Jokinen). All 3D examinations and the analyses of echocardiographic measurements were carried out by one observer (A. Eerola).z-scores of thicknesses of interventricular septum and posterior wall of LV, and those of RV and LV end-diastolic dimensions were determined [Two-dimensional echocardiography with color flow Doppler was used to evaluate the cardiac anatomy and to measure the size of ASD. M-mode echocardiography was performed from either the parasternal long-axis or short-axis views. RV end-diastolic and LV end-diastolic and end-systolic dimensions were measured, and LV volumes, fractional shortening, and ejection fraction calculated. The termined . The meaThree-dimensional echocardiography was performed with TomTec computer software system, as described earlier in . The timCardiac catheterization with hemodynamic evaluation and angiography was performed under general endotracheal anesthesia, systemic heparinization, and antimicrobial prophylaxis. In patients with ASD, the procedure was also guided by transesophageal echocardiography. For ASD closure, either the Amplatzer Septal Occluder  or the Helex Septal Occluder  was used. The PDA was occluded with either Flipper detachable coil  or with an Amplatzer Duct Occluder . In patients with CoA, percutaneous angioplasty was performed using either balloon dilatation only or with stent implantation.Surgical closure of ASD was performed via midline sternotomy with direct suture using normothermic cardiopulmonary bypass. Repair of CoA was performed with resection and end-to-end anastomosis from left thoracotomy.P < .05.Analyses were performed with the Statistical Package for Social Science version 12.01 for Windows . For variables derived from blood samples, median and range were calculated. Because distribution of parameters tested by Kolmogorov-Smirnov's goodness-of-fit test was not normal, the Mann-Whitney test was used for statistical analysis between groups, and the Wilcoxon Signed-Rank Test for analysis within groups. Spearman's correlation coefficient was used for calculating correlations between the echocardiographic measurements of chamber dimensions and serum concentrations of ANPN and NT-proBNP. The level of significance was Of the 21 children with ASD, 14 were treated with device closure and 7 with operation. The size of the defect measured a median of 12 (range 7–21) mm in transthoracic echocardiography. No other heart defects were observed. The ASD was closed with the Amplatzer Septal Occluder  in 12 patients and with the Helex Septal Occluder  in 2 patients. After closure, no residual shunt was evident at the 6- or 12-month follow-up in transthoracic echocardiography.At baseline, children with ASD had higher serum levels of both ANPN and NT-proBNP than controls ; Table 2P < .001) but equal to controls at the 6- and 12-month follow-ups. Similarly, the end-diastolic and systolic volumes of LV increased in 3D echocardiography during follow-up  and in 7 with an Amplatzer Duct Occluder . In these children, no other heart defects were observed. One child had a minimal residual shunt 6 months after coil occlusion. Children with PDA had higher levels of ANPN and NT-proBNP than controls before occlusion of PDA. After intervention, levels of both peptides decreased but were still somewhat higher than in controls at the 6-month follow-up , Table 2P = .001) at the 6-month follow-up. Systolic blood pressure measured a median of 120 (range 96–151) mm Hg in patient group and 101 (range 72–123) mm Hg in controls (P < .001). During the 12-month follow-up, it decreased to a median of 105 (range 83–117) mm Hg in patients (P = .001 compared with baseline) and did not differ from that of controls.Of the 15 children with CoA, 11 had native CoA and 4 recurrent CoA after surgery. Ten patients had a bicuspid aortic valve and one patient had mild mitral valve regurgitation. Five patients underwent balloon dilatation, one of them with a stent implantation. Ten patients were operated on with resection and end-to-end anastomosis. At baseline, the arm-leg blood pressure gradient measured a median of 30 (range 20–56) mm Hg. It decreased to a median of 3 (range 0–16) mm Hg , followed by those with ASD (P = ns as compared with patients with CoA), and finally those with CoA. ANPN levels at baseline were similar in all patient groups, but higher in these than in controls.Among patients older than 6 months, levels of NT-proBNP were the highest in children with PDA . In patients with PDA and volume overload of the left side of the heart, serum levels of ANPN and pro-BNP correlated with LV end-diastolic diameter  and volume  in 2D echocardiography. In patients with CoA, negative correlations were found between levels of ANPN and NT-proBNP and 3D echocardiographic end-diastolic volume of LV .At baseline, serum levels of ANPN and NT-proBNP correlated with 2D and 3D echocardiographic dimensions of RV and LV according to the loading condition. In the ASD group, serum levels of NT-proBNP correlated with the end-systolic volume of LV  than in right- sided volume overload . In our Plasma levels of BNP have been shown to correlate with right atrial and ventricular pressures in a child population consisting of different loading conditions and a wide age range . In adulThe most significant limitation to this study is that the number of patients in each group of patients is small and therefore we cannot compare the patients undergoing surgical and percutanoeus treatment. The age range is wide in patient groups and controls. The controls were examined only once. However, we assumed that the levels of peptides would not change significantly during one year. In conclusion, serum levels of both ANPN and NT-proBNP are higher in patients with ASD or PDA than in controls. In patients with CoA, ANPN levels are higher than in controls. After treatment, peptide levels decrease and some remodeling of the originally loaded ventricle takes place during within 6–12 months. Natriuretic peptide levels correlate with echocardiographic findings and reflect the hemodynamic loading condition. Therefore, natriuretic peptides might be useful in the pre-and postoperative follow-up of these patient groups.


In patients with advanced non-ischemic cardiomyopathy (NIC), right-sided cardiac disturbances has prognostic implications. Right coronary artery (RCA) flow pattern and flow reserve (CFR) are not well known in this setting. The purpose of this study was to assess, in human advanced NIC, the RCA phasic flow pattern and CFR, also under right-sided cardiac disturbances, and compare with left coronary circulation. As well as to investigate any correlation between the cardiac structural, mechanical and hemodynamic parameters with RCA phasic flow pattern or CFR.Twenty four patients with dilated severe NIC were evaluated non-invasively, even by echocardiography, and also by cardiac catheterization, inclusive with Swan-Ganz catheter. Intracoronary Doppler (Flowire) data was obtained in RCA and left anterior descendent coronary artery (LAD) before and after adenosine. Resting RCA phasic pattern (diastolic/systolic) was compared between subgroups with and without pulmonary hypertension, and with and without right ventricular (RV) dysfunction; and also with LAD. RCA-CFR was compared with LAD, as well as in those subgroups. Pearson's correlation analysis was accomplished among echocardiographic  more hemodynamic parameters with RCA phasic flow pattern or RCA-CFR.LV fractional shortening and end diastolic diameter were 15.3 ± 3.5 % and 69.4 ± 12.2 mm. Resting RCA phasic pattern had no difference comparing subgroups with vs. without pulmonary hypertension  either with vs. without RV dysfunction ; RCA vs. LAD was 1.35 vs. 2.85 (p < 0.001). It had no significant correlation among any cardiac mechanical or hemodynamic parameter with RCA-CFR or RCA flow pattern. RCA-CFR had no difference compared with LAD , as well as in pulmonary hypertension  either in RV dysfunction  subgroups. In patients with chronic advanced NIC, RCA phasic flow pattern has a mild diastolic predominance, less marked than in LAD, with no effects from pulmonary artery hypertension or RV dysfunction. There is no significant correlation between any cardiac mechanical-structural or hemodynamic parameter with RCA-CFR or RCA phasic flow pattern. RCA flow reserve is still similar to LAD, independently of those right-sided cardiac disturbances. In recent years, interest in cardiac right sided compromise in heart failure (HF) due to dilated cardiomyopathy has increased, mainly because of its prognostic implications ,2. The rIn HF physiopathology, several mechanical and hemodynamic disturbances can affect both right and left cardiac chambers but in different ways -6. In riThe phasic coronary flow pattern, in dogs under normal intracavitary pressures, presents systolic flow predominance over diastolic flow in right coronary artery (RCA), inversely to left anterior descendent coronary artery (LAD) ,9. PartiIn patients with HF resulting from chronic dilated advanced NIC, it is not known if and how RCA flow pattern and reserve are affected, even in comparison with LAD.The purposes of this study were to evaluate the phasic flow pattern and coronary flow reserve in RCA in patients with chronic dilated non-ischemic cardiomyopathy and severe LV dysfunction, the possible influences from pulmonary arterial hypertension and RV dysfunction in this setting, and to compare these parameters to those obtained in left coronary circulation. As well as, to investigate any correlation among the cardiac structural, mechanical and hemodynamic parameters with RCA phasic flow pattern and CFR.This study included twenty-four patients with non-ischemic dilated cardiomyopathy and severe left ventricular (LV) dysfunction, who have consented to be submitted to non-invasive and invasive cardiac evaluation. The cardiovascular medications used, according to clinical indications, were basically diuretics, digitalics, angiotensin-converting enzyme inhibitors and alpha-methyldopa; no patient was in use of beta-blockers, xantine contents or anticoagulants. Concerning cardiomyopathy etiologies, we had 12 patients with hypertensive cardiomyopathy, five with chagasic, and seven with dilated idiopathic cardiomyopathy. The inclusion criteria were presence of cardiomyopathy with LV diffuse hypokinesia and severe systolic dysfunction defined by LV fractional shortening ≤ 20%, evaluated by echocardiography , in patiThe study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Hospital's Ethic Committee. All patients have given their written informed consent after clarification of all steps of the study.After clinical and laboratorial evaluation, the patients were submitted to 12-lead ECG, 2D-Doppler echocardiography, and RV radionuclide ventriculography. Afterwards, the patients were submitted to cardiac catheterization, coronary angiography, and intracoronary Doppler study in both RCA and LAD.To compare parameters we also divided the patients in subgroups according to pulmonary artery systolic pressure (PASP) and according to RV function.The echocardiograms were performed in the Hospital setting, in same period of invasive study, employing a Sequoia™ 512  echocardiography equipment, with a broad-band transducer.The LV dimensions, regional and global function evaluations were performed using two-dimensional and M-mode approaches accordingly to the American Society of Echocardiography ,21 and ain vivo technique. Data were acquired in an ECG-synchronized frame mode  in a 64 × 64 computer matrix. Multiple-gated equilibrium blood pool imaging was performed at rest to determine global RV EF.Radionuclide ventriculography was performed to quantify the RV ejection fraction (EF) ,26. The According to RV EF values we separated two groups for data comparison, one considered with effective RV dysfunction, RV EF < 0.35 (12 patients), and other named with preserved function, RV EF > 0.35 (12 patients).Just before the coronary angiography, right and left cardiac catheterization were done, according Judkins technique, and also it was obtained measurements by a Swan-Ganz catheter  with support of a data register . A cardiac catheterization equipment H-3000  was employed.The cardiovascular medications were suspended 24 hours before the study according to the clinical individual condition. The patients were advised to not use xantines, caffeine, or cola contents, in the preceding 24 hours.The PASP was assumed to be the same as the systolic RV pressure once in the absence of ventricular obstruction . A PASP All patients underwent selective coronary angiography using a 7F standard catheters and proceeding conventional views. On completion of diagnostic cardiac catheterization, the digital record of the procedure was reviewed. Only patients whose coronary arteries were angiographically normal were enrolled in the study. It was used a quantitative angiographic digital analysis system  to analyze coronary lumen . Right c®, EndoSonics, Inc., Rancho Cordova, California, USA) was advanced through the catheter to the proximal LAD, away at least 10 mm from a septal branch, and then to proximal RCA. Baseline flow-velocity measurements were performed once a stable Doppler signal was obtained. Frequency analysis of the Doppler signals was carried out in real time by fast Fourier transform using a velocimeter . Over the Doppler envelope was calculated the time-average peak flow velocity (APV) obtained from the last two cardiac cycles as the image was frozen. The Doppler velocity signals were displayed along with simultaneous ECG and aortic pressure waveforms, and the envelopes were automatically analyzed using the FloMap® equipment system. All registers were printed and recorded on videotape. Once baseline flow-velocity data had been obtained, we have used the best signal resulting from two ways to obtain the maximal hyperemic signal: i.e., a bolus injection of intracoronary adenosine , 18 μg for LAD and 12 μg for RCA, and after a wash-out step, an intravenous adenosine continuous infusion (140 μg/kg/min) [®, Anesthesia Infusion System, Abbott Laboratories, Illinois, USA) to LAD and RCA evaluations, respectively. The CFR equivalence from these two acquisitions ways is already established [Consecutively to coronary angiography, the left and right coronary arteries (in random order) were selectively engaged with a diagnostic catheter. All patients received 7500 IU bolus of heparin, and also an intracoronary 5 mg isosorbide-5-mononitrate bolus was done before the procedure to prevent catheter-induced coronary artery spasm and to minimize changes in coronary artery diameter . The Dop/kg/min) ,32, emplablished ,32. The ablished . The phaData were expressed as mean values ± SD. Non-parametric Mann-Whitney test was used to compare the mean values of two subgroups (independent samples). Non-parametric Wilcoxon test was used to compare two conditions in the same group (related samples). The data were also represented in box-plots expressed as median ± SE. The Pearson's correlation was employed for the measurement of association between the different analyzed variables. A probability value of less than 0.05 was considered as statistically significant. A computer analysis system SPSS software version 8.0  was employed to support the statistical analysis.We enrolled twenty-four patients with dilated non-ischemic cardiomyopathies and severe LV dysfunction, 15 men, with mean age 50.7 ± 10 years, all with symptoms more than one year and heart failure functional class (NYHA) II or III, by occasion of the evaluation. The LV echocardiography variables are shown in Table Table The right coronary circulation dominance was present in 96% of patients. No patients had coronary obstructions. We had no major complications in any invasive procedure.Our results showed a resting mild diastolic predominance on RCA phasic flow pattern (diastolic/systolic APV ratio = 1.35); this RCA diastolic/systolic phasic flow pattern was significantly lesser than in LAD , as represented in Figure RCA flow reserve was not different in comparison to LAD , as showed in Figure This study is first evaluating RCA flow velocity pattern and flow reserve in patients with HF resulting from advanced non-ischemic cardiomyopathy, employing invasive spectral Doppler technique. We showed that in these patients RCA phasic flow pattern has still a mild diastolic predominance, contrarily from verified experimentally -9, and tIn fact, most of reported studies involving RCA phasic flow or CFR in this HF setting is experimental. In human with non-obstructive coronary disease, the vast majority of investigations refers to patients with others cardiopathies or even to normal subjects, or employing another techniques, or just focusing only LAD -19, limiOur findings showed a mild diastolic predominance in RCA flow pattern Figs.  and 2, dIn our study, the LAD diastolic flow predominance was marked, compatible with expected LV mechanics influence Figs.  and 2. IRCA dominance is present in majority of humans , as it wRight cardiac side has several structural and functional differences from left cardiac side -6. For eIndependently of inherent mechanical and hemodynamic differences between right and left cardiac sides in advanced heart failure due to dilated non-ischemic cardiomyopathy -4,6,40, We have employed adenosine, to provoke hyperemia, that is fundamentally an endothelium-independent stimulant and acts at arteriolar level . Thus, iper se [The presence of pulmonary arterial hypertension has also a prognostic role in advanced HF patients . When weper se ,4. Apartper se -5. It isper se . TherefoAlthough it has not been object of the present study, the absolute increment verified on CFR merits some considerations. Firstly, we had no control group to compare with and thus to endorse these findings. Secondly, even though we had analyzed advanced non-ischemic cardiomyopathies, the different etiologies could have a role in our findings. In fact, few studies have evaluated CFR in Chagas' disease. Torres et al. have found a marked reduction of CFR with acetylcholine, not paralleled with the adenosine infusion . We haveThis study demonstrated how is the RCA flow behavior in conditions of HF in advanced non-ischemic dilated cardiomyopathy. Although the RCA phasic flow pattern had been different from that evidenced in experimental studies ,9, we meRespecting CFR, by these results we can infer that is possible to extrapolate the findings from LAD to RCA, or vice versa, in this setting of patients. Generally it is easier to explore the CFR in left coronary circulation (LAD) due to its topography -19, evenThis study had some limitations. Regarding the different cardiomyopathy etiologies, we have considered that as the aim was determine fundamentally the cardiac mechanical and hemodynamic repercussions in coronary flow dynamics, we have emphasized mostly the advanced structural stage from chronic non-ischemic cardiomyopathies, independently of its etiology. Normal subjects were not evaluated due to ethical issues. Another limitation is the number of patients; however, the invasive nature of studies, additionally its high costs, and sufficient statistical basis, made this number of patients enough. Concerning the two methods of hyperemia induction, which are equivalents according other pertinent studies ,32, we hIn patients with chronic non-ischemic dilated cardiomyopathy and severe LV dysfunction, the RCA phasic flow pattern has yet a mild diastolic predominance, less marked than LAD, and it is not significantly influenced by presence of pulmonary hypertension or RV dysfunction. Neither RCA phasic flow pattern nor RCA-CFR presented significant correlation with any cardiac structural, mechanical or hemodynamic parameter. RCA flow reserve is similar to LAD in these patients, even in presence of pulmonary arterial hypertension or RV dysfunction. In this setting of patients, it could be reasonable to extend to RCA the flow reserve parameters acquired from LAD, where they are more easily obtainable even non-invasively with echocardiography.APV – time-averaged peak flow velocityCFR – coronary flow velocity reserveEF – ejection fractionHF – heart failureLAD – left anterior descending coronary arteryLV – left ventricle/ventricularPASP – pulmonary artery systolic pressureRCA – right coronary arteryRV – right ventricle/ventricularThe author(s) declare that they have no competing interests.PG participated of study's conception and design, performance of echocardiograms, clinical and scientific support during intracoronary Doppler and hemodynamic exams; data interpretation and wrote the manuscript. BI participated in the clinical support, data acquisition, and critically manuscript revising. ER, MP and LB participated in hemodynamic exam performance and giving important suggestions. CMe coordinated the nuclear medicine exams. CMa participated in clinical support coordination and gave important contributions. EMF participated in hemodynamic exam performance and gave important suggestions. JAFR participated of study's conception and design, data interpretation, and critically manuscript revising for important intellectual content. All authors have read and approved the final manuscript.


Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy.This combination of lesions occurs in 3 of every 10,000 live births, and accounts for 7–10% of all congenital cardiac malformations.Patients nowadays usually present as neonates, with cyanosis of varying intensity based on the degree of obstruction to flow of blood to the lungs.The aetiology is multifactorial, but reported associations include untreated maternal diabetes, phenylketonuria, and intake of retinoic acid. Associated chromosomal anomalies can include trisomies 21, 18, and 13, but recent experience points to the much more frequent association of microdeletions of chromosome 22. The risk of recurrence in families is 3%.Useful diagnostic tests are the chest radiograph, electrocardiogram, and echocardiogram. The echocardiogram establishes the definitive diagnosis, and usually provides sufficient information for planning of treatment, which is surgical. Approximately half of patients are now diagnosed antenatally.Differential diagnosis includes primary pulmonary causes of cyanosis, along with other cyanotic heart lesions, such as critical pulmonary stenosis and transposed arterial trunks. Neonates who present with ductal-dependent flow to the lungs will receive prostaglandins to maintain ductal patency until surgical intervention is performed. Initial intervention may be palliative, such as surgical creation of a systemic-to-pulmonary arterial shunt, but the trend in centres of excellence is increasingly towards neonatal complete repair. Centres that undertake neonatal palliation will perform the complete repair at the age of 4 to 6 months. Follow-up in patients born 30 years ago shows a rate of survival greater than 85%. Chronic issues that now face such adults include pulmonary regurgitation, recurrence of pulmonary stenosis, and ventricular arrhythmias. As the strategies for surgical and medical management have progressed, the morbidity and mortality of those born with tetralogy of Fallot in the current era is expected to be significantly improved. La Maladie Bleue, as described by Louis Arthur Etienne Fallot in 1888 . Each coTetralogy of Fallot occurs in 3 of every 10,000 live births. It is the commonest cause of cyanotic cardiac disease in patients beyond the neonatal age, and accounts for up to one-tenth of all congenital cardiac lesions [The embryological basis of the combination of lesions is antero-cephalad deviation of the developing outlet ventricular septum, or its fibrous remnant should this septum fail to muscularise. Such deviation, however, can be found in the absence of subpulmonary obstruction, as in the so-called Eisenmenger ventricular septal defect . So as tAs discussed above, the interventricular communication found in tetralogy of Fallot exists because of the anterior and cephalad malalignment of the outlet portion of the muscular ventricular septum, or of its fibrous remnant should the outflow cushions fail to muscularise during embryonic development. The resulting hole is one of a number of those appropriately described as a malalignment defect. In four-fifths of Caucasians with such a defect, the postero-inferior margin of the hole between the ventricles is formed by an area of fibrous continuity between the leaflets of the aortic and tricuspid valves, also involving the remnant of the interventricular portion of the membranous septum . In thesIn a small proportion of Caucasian patients, but in larger numbers of patients seen in the Far East, and in Central and South America, the antero-superior margin of the ventricular septal defect is not formed by the muscular outlet septum, but is formed by fibrous continuity between the leaflets of the aortic and pulmonary valves. This morphology is the consequence of failure of muscularisation of the developing outlet septum Figure . These pThe size of the ventricular septal defect can vary, but in almost all instances, the interventricular communication is unrestrictive, allowing for bidirectional shunting .Because of the displacement of the malaligned outlet septum into the right ventricle, the aortic root, of necessity, overrides the muscular ventricular septum. In the setting of significant subpulmonary obstruction, shunting across the interventricular communication is predominantly from right-to-left, which promotes ejection of deoxygenated blood into the systemic circulation. The chronic volume load sustained by the overriding aorta is implicated in the dilation of the aortic root noted in adults with tetralogy of Fallot ,8.The antero-cephalad deviation of the outlet septum, coupled with an anomalous relationship to the septoparietal trabeculations, results in a narrowing of the subpulmonary outflow tract. The obstructive muscular subpulmonary area thus created is a dynamic entity. The degree of stenosis created can be exacerbated by catecholamines, or a state of low intravascular volume, predisposing the patients to sudden and acute episodes of desaturation known as hypercyanotic spells ,10.The obstruction to flow into the lungs often extends beyond the subpulmonary outflow tract itself. The pulmonary valve may be hypoplastic, with abnormally functioning leaflets, often having a bifoliate configuration. Not infrequently, the pulmonary trunk, and the right and left pulmonary arteries, are diminutive, exhibiting additional focal areas of narrowing .This lesion is at the most severe end of the spectrum of antero-cephalad deviation of the outlet septum. Occasionally, however, the pulmonary valve is affected in isolation, being imperforate rather than stenotic. In approximately half of patients with pulmonary atresia, the right and left pulmonary arteries are confluent, with blood to the pulmonary arteries flowing through the persistently patent arterial duct. In the other half, the pulmonary arterial supply is multifocal. In these patients, if the pulmonary arteries are confluent or continuous, the blood supply will likely originate only from multiple aorto-pulmonary collateral arteries Figure . If the Although the collateral arteries do not depend on prostaglandin for patency, they have the potential to stenose over time. In other instances, large collateral arteries can provide unrestricted flow to the lungs, thus producing hypertensive pulmonary vasculature. The long-term management of the pulmonary supply in patients with tetralogy of Fallot and pulmonary atresia, therefore, is complicated.Malalignment of the outlet septum with rudimentary formation of the leaflets of the pulmonary valve, so-called absent pulmonary valve syndrome, is seen in around one-twentieth of those alleged to have tetralogy of Fallot . The preWith pronounced aortic override, the aorta becomes more committed to the right ventricle than to the left ventricle, resulting in many instances in the ventriculo-arterial connection of double outlet right ventricle. Although the physiology on presentation may not be altered, there are important implications for surgical repair . PatientAn atrioventricular septal defect combined with a common atrioventricular junction is found in 2% of patients with tetralogy of Fallot . The preAnomalous origins of the coronary arteries occur in up to one-sixth of patients, and should be documented prior to surgical repair. The most common and relevant anomaly is origin of the left anterior descending artery from the right coronary artery, with the anomalous artery then coursing anterior to the subpulmonary outflow tract, a potential site of surgical incision.Other associated lesions include atrial septal defects, and additional ventricular septal defects, the latter usually being muscular. Straddling and overriding of the tricuspid valve may also occur, which will complicate the closure of the ventricular septal defect. An important finding when there is overriding of the orifice of the tricuspid valve is the anomalous location of the atrioventricular conduction tissues . A rightThe initial presentation of tetralogy of Fallot varies depending on the severity of the obstruction of blood flow to the lungs. Most patients will present in the neonatal period with mild-to-moderate cyanosis, but typically without respiratory distress. More uncommonly, patients with very mild right ventricular outflow tract obstruction at birth may be diagnosed at a couple months of age as the obstruction worsens resulting in newly noticed cyanosis and a louder murmur. Because patients with tetralogy of Fallot have obstruction to pulmonary blood flow, they will not present with signs of heart failure such as failure to thrive. Irritability and lethargy are rarely seen in patients with tetralogy of Fallot except in the setting of a hypercyanotic spell. Clubbing is also highly unusual in the modern era since newly diagnosed patients undergo surgical repair before clubbing has time to develop.The second heart sound in patients with tetralogy of Fallot may be single and loud, and a harsh systolic ejection murmur will be present, emanating from the obstructed subpulmonary outflow tract. Flow across the interventricular communication in tetralogy of Fallot is usually not turbulent, and therefore not audible. Patients with severe obstruction, and very little antegrade flow across the subpulmonary outflow tract, will be more significantly cyanotic and have a less prominent murmur.Once the lesion is suspected, an electrocardiogram and chest radiograph should be performed. The electrocardiogram will demonstrate right axis deviation and prominent right ventricular forces, with large R waves in the anterior precordial leads and large S waves in the lateral precordial leads . AlthougDiagnosis is confirmed with echocardiography. The severity of the subpulmonary obstruction, its dynamic component, the size of the right and left pulmonary arteries, and any additional sources of flow of blood to the lungs will all be delineated Figures , 7a, 7b.The hypercyanotic spell ,10 is chThe aetiology is multifactorial. Associated chromosomal anomalies can include trisomies 21, 18, and 13, but recent experience points to the much more frequent association of microdeletions of chromosome 22. As many as one-eighth of patients will have chromosomal abnormalities, such as trisomy 21, 18, or 13 ,20,21. TThe risk of recurrence in a family is approximately 3%.Associations with maternal intake of retinoic acid during the first trimester, poorly controlled diabetes, and untreated phenylketonuria have also been described .Tetralogy of Fallot can be diagnosed antenatally as early as 12 weeks of gestation . In a poThe differential diagnosis of any cyanotic patient with a murmur will include persistent pulmonary hypertension of the newborn, as well as other cyanotic lesions such as critical pulmonary stenosis, Ebstein's malformation, transposed arterial trunks, common arterial trunk, totally anomalous pulmonary venous connection, and tricuspid atresia.Clinical management is determined by the degree and type of subpulmonary obstruction, in combination with the preference of the centre for the timing of surgical intervention. Depending on the severity of obstruction within the subpulmonary outflow tract, an infusion of prostaglandin may be initiated to preserve ductal patency, and provide a stable source of flow of blood to the lungs. Patients who require such an infusion will most likely require surgical intervention prior to discharge from the hospital. For those patients who have adequate forward flow through the subpulmonary outflow tract after ductal closure, management consists of close follow-up until a complete repair is performed.Some centres will perform complete repairs in all neonates. Others will palliate symptomatic neonates, and perform a complete repair in all patients at the age of 4 to 6 months.Palliation, which frequently does not require cardiopulmonary bypass, establishes a secure source of flow of blood to the lungs by placing a prosthetic tube between a systemic and a pulmonary artery. The most common type of aorto-pulmonary shunt is known as the modified Blalock-Taussig shunt. This consists of a communication between a subclavian and pulmonary artery on the same side. A complete repair, always performed under cardiopulmonary bypass, consists of closing the interventricular communication with a patch channeling the left ventricle to the aortic root, relief of the subpulmonary obstruction, and reconstruction, if necessary, of the pulmonary arteries.Complete neonatal repair provides prompt relief of the volume and pressure overload on the right ventricle, minimises cyanosis, decreases parental anxiety, and eliminates the theoretical risk of stenosis occurring in a pulmonary artery due to a palliative procedure. Patients who undergo a successful complete repair during the neonatal period will be unlikely to require more than one intervention in the first year of life, but are not free from reintervention. Concerns regarding such neonatal complete repairs include exposure of the neonatal brain to cardiopulmonary bypass, and the increased need to place a patch across the ventriculo-pulmonary junction when compared to older age at repair ,25. PatcIn summary, patients with cyanotic tetralogy of Fallot will either undergo neonatal complete repair or neonatal palliation with an aortopulmonary shunt followed by a complete repair at four to six months of age. Peri-operative mortality rates for either surgical approach is less than 3% ,25 and sNeonates born with tetralogy of Fallot with pulmonary atresia who do not have stable flow to the lungs through collateral arteries will require surgical intervention prior to discharge from the hospital. In newborns with tetralogy of Fallot with absent pulmonary valve, surgical repair may be required prior to initial discharge from hospital if obstruction to the airways is a prominent symptom. In cases with tetralogy of Fallot with atrioventricular septal defect, complete repair is usually performed later in life compared to patients with uncomplicated tetralogy of Fallot, typically between the ages of 6 and 12 months. If significantly cyanotic at birth, most centres still opt for initial palliation rather than complete repair in these patients. Freedom from reoperation is decreased compared to patients with uncomplicated tetralogy of Fallot .Overcoming a hypercyanotic spell requires maneuvers to re-establish adequate balance between the systemic and pulmonary flows. Treatment must focus on decreasing pulmonary, and increasing systemic, vascular resistance, hence promoting left to right flow across the ventricular septal defect and into the subpulmonary outlet.Parents at home with a child suffering such spells are taught to place their child in the knee-to-chest position in an effort to increase systemic vascular resistance and promote systemic venous return to the right heart. This will theoretically increase intracardiac shunting from left-to-right across the interventricular communication, as well as increase the preload of the right ventricle. Emergency services should be contacted immediately.Medical management will consist of establishing immediate intravenous access to allow prompt administration of fluids, which will improve right ventricular preload. Oxygen should be initiated to decrease peripheral pulmonary vasoconstriction, and improve oxygenation once flow of blood to the lungs is re-established. Subcutaneous morphine should be administered to decrease the release of catecholamines. This will increase the period of right ventricular filling by decreasing the heart rate, and promote relaxation of the infundibular spasm. If the patient remains hypercyanotic after these measures, he or she should be paralysed and intubated, with phenylephrine administered intravenously to increase systemic vascular resistance.The long half-life, and potential side effects, such as hypotension and cardiac dysfunction, of beta blockers precludes their routine use in the emergency situation. Propranolol has been used in small doses in the chronic care of patients deemed to be at risk for spells in an effort to minimise the infundibular spasm responsible for the episodes. Once a patient requires prophylaxis by beta-blockade, surgical referral should occur to prevent the potential tragic and unpredictable outcome of a hypercyanotic spell .Studies of immediate and long-term follow-up in tetralogy of Fallot reveal excellent outcomes. Patients born 30 years ago with tetralogy of Fallot have an 85% long-term rate of survival, and in the absence of serious residuae are able to lead normal lives as evidenced by the ability to carry successful pregnancies for example -40. ChroQuestions that remain regarding the management of tetralogy of Fallot pertain to the preference of surgical timing, as discussed above, and to the residual lesions of the disease. The management of young adults with pulmonary regurgitation or residual pulmonary stenosis is complex. A balance must be achieved between limiting the haemodynamic burden on the right ventricle, and minimizing the life-time number of surgical interventions required for a given patient. Cardiac magnetic resonance imaging has progressed significantly in the past ten years Figures  and 9b.


T-wave alternans (TWA) has been employed in the selection of patients considered for cardioverter/defibrillator (ICD) implantation, and has been found to have an excellent negative predictive value for sudden death and malignant ventricular arrhythmias in patients with a variety of cardiac pathologies . AlthougIt has been speculated that the magnitude of the TWA may be T-wave amplitude dependent , and thu In a recent article, Paz et al  reportedEven if the suggestion to evaluate whether T wave alternans is T wave amplitude dependent is implemented, and leads to a TWA index with improved performance, we will still be left with a major subset of patient population in whom risk stratification for sudden cardiac death cannot be done, because mainly the results of the TWA assessment had been indeterminate. Reducing the percentage of indeterminate results would be a major scientific advancement. However one cannot predict whether sensitivity and specificity of TWA would increase by taking into account the T-wave attributes, until this hypothesis is tested. It is possible that some of the indeterminate results are secondary to these T-wave attributes, and thus adjustment for such amplitudes may enhance the chances of getting a determinate result. However there is no proof for such hypothesis either. Certainly many patients end up with a TWA indeterminate result for the plain reason that their ECG comprised excessive arrhythmic activity, or they cannot attain during exercise the necessary rise of their heart rate required for TWA assessment. Finally one cannot foresee what would be the impact of metabolic abnormalities, e.g., hyperkalemia, or cardiac memory, due to pacing, transient episodes of intraventricular blocks, or ventricular tachycardia, on a TWA index.


Right ventricular dilatation in the setting of acute pulmonary embolism is associated with an adverse prognosis. Treatment with a pulmonary vasodilator has never been studied systematically. We evaluated the effect of epoprostenol on right ventricular diameter and function in patients with acute pulmonary embolism and right ventricular dilatation.In a randomized, single-blind study, 14 patients with acute pulmonary embolism received epoprostenol or placebo infusion for 24 hours on top of conventional treatment. Effects on right ventricular end-diastolic diameter, systolic pulmonary artery pressure, right ventricle fractional area changeand tricuspid annular plane systolic excursion were assessed by serial echocardiography. Furthermore Troponin T and NT-proBNP were measured serially.Compared to placebo, epoprostenol was associated with a relative change from baseline in right ventricular end-diastolic diameter of +2% after 2.5 hours and -8% after 24 hours. Epoprostenol did not have a significant effect on systolic pulmonary artery pressure, right ventricular fractional area change and tricuspid annular plane systolic excursion, nor on biochemical parameters.In patients with acute pulmonary embolism and right ventricular overload, treatment with epoprostenol did not improve right ventricular dilatation or any other measured variables of right ventricular overload.Registration: URL: NCT01014156Medical ethical committee: Medisch-ethische toetsingscommissie (METc) from the VUmc  Pulmonary embolism is a frequent and potentially fatal disorder. Despite immediate treatment with anticoagulants, morbidity and mortality are still high when hemodynamically stable patients with pulmonary embolism have echocardiographic signs of acute right ventricular overload -3.An acute increase in right ventricular afterload is the hallmark of severe pulmonary embolism, and is responsible for many of its clinical manifestations and complications. The traditional view is that mechanical obstruction by thrombus mass causes pulmonary hypertension. Therefore, treatment focusses on relieving mechanical obstruction, either by anticoagulation if patients are stable, or by thrombolytic therapy in case of hemodynamic instability . The optApart from mechanical obstruction, vasoconstriction of the pulmonary vasculature plays a pivotal role in the acute rise in pulmonary artery pressure in patients with pulmonary embolism . This isGiven the role of pulmonary vasoconstriction in the pathogenesis of pulmonary embolism-associated pulmonary hypertension, the potential benefit of pulmonary vasodilators is important. There is experimental evidence suggesting that antagonising pulmonary vasoconstriction by administration of selective vasodilators is beneficial. In animal models of acute pulmonary embolism prostacyclin, a relatively selective pulmonary vasodilator, prevented or partially reversed the rise in pulmonary vascular resistance and pressure ,15. PretIn this randomized, controlled trial, we evaluated the effects of epoprostenol, the pharmacological form of prostacyclin, on echocardiographic abnormalities, cardiac biomarkers and on hemodynamic and respiratory symptoms in patients with pulmonary embolism with echocardiographic signs of right ventricular overload.2 <80 mmHg (with oxygen supplementation of 2 liters), peripheral oxygen saturation (SaO2) <95% or dyspnea [A total 82 patients with acute pulmonary embolism, as diagnosed by spiral CT, were screened for eligibility. Patients were potentially eligible if they had a recent (<24 hours) onset or progression of symptoms, and if the clinical probability of finding right ventricular overload by echocardiography was high, as indicated by one of the following symptoms or signs: (near) collapse, systolic blood pressure <100 mmHg, diastolic blood pressure <60 mmHg, pulse rate >100 beats/min, elevated jugular venous pressure, electrocardiographic abnormalities , tachypnea (breathing frequency >20/min), PaO2, circulatory shock (blood pressure <80/45 mmHg), mechanical ventilation, treatment with thrombolytic therapy, placement of a vena cava filter, atrial fibrillation or severe pre-existent cardiopulmonary disease .After informed consent was obtained, patients were screened by transthoracic echocardiography for signs of pulmonary hypertension. If acute right ventricle dilatation was present (right ventricular end-diastolic diameter (RVED) >30 mm ,18 in thThe study protocol was approved by the local ethics committee (METc), and written informed consent was obtained from each patient prior to study entry.®; GSK; Zeist, the Netherlands) or saline placebo infusion. Infusion of epoprostenol was started in a dose of 1 ng/kg/min. Every 10 minutes the dose was increased with 1 ng/kg/min to a maximum dose of 4 ng/kg/min. Patients not randomised to epoprostenol received a similar syringe pump containing isotonic saline. During titration of epoprostenol infusion, blood pressure, pulse rate and peripheral oxygen saturation were measured at 5 minute intervals. If, during titration, mean blood pressure dropped by >10 mmHg, the dose of epoprostenol was not further increased and 0.5 liter of extra sodium chloride was administrated in 30 minutes. If blood pressure dropped by >15 mmHg or if oxygen saturation dropped by >7% (or absolute <85%) epoprostenol infusion was decreased to the previous titrated dose. If blood pressure and/or oxygen saturation were not restored by down-titration, epoprostenol infusion was stopped. After inclusion of the first 8 subjects, no side effects of epoprostenol treatment at a dose of 4 ng/kg/min were observed. Because our study is a proof-of-principle study we decided to increase epoprostenol infusion rate every 10 minutes with 1 ng/kg/min to the maximum dose of 8 ng/kg/min, which is substantially higher than maximum initial doses used in epoprostenol intervention trials in patients with chronic pulmonary hypertension [2 were assessed hourly for the entire duration of epoprostenol or placebo infusion. Epoprostenol infusion was continued for 20 hours, then tapered gradually during 4 hours and stopped. Hence, total treatment with epoprostenol or placebo encompassed a period of 24 hours.Patients were randomized to receive intravenous epoprostenol sodium  and a isotonic saline infusion (80 ml/hr).2 as a sign of intrapulmonary shunting due to epoprostenol infusion. The primary end point was the change in RVED between baseline measurement and during treatment (i.e. measurements 2 and 3). Secondary end points were right ventricular diameter 48 hours after treatment was stopped (i.e. measurement 4), systolic PAP, tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RVFAC), serum cardiac troponin T and NT-proBNP.At baseline, after 2.5, 24 and 72 hours echocardiographic parameters were obtained. At baseline, after 4, 24 and 72 hours serum creatine kinase, cardiac troponin T and NT-proBNP were measured. At baseline, after 4 and 24 hours, arterial blood gas analysis was performed to detect hypoxemia or a rise in PaCOStandard two-dimensional and Doppler echocardiography was performed with a commercially available Vivid 7 system  using a 3.0 Mhz broadband (M3S) transducer; serial echocardiograms were analysed off-line. All examinations included standard parasternal, apical and subcostal views and were stored digitally for subsequent analysis. Right ventricular function was assessed by TAPSE and RVFAC, right ventricular dimensions by long axis and tricuspid annular size from the apical 4 chamber view. Furthermore, estimation of systolic PAP was obtained by peak tricuspid regurgitant jet with continuous wave Doppler and adding the right atrial pressure derived from the collapse index of the inferior vena cava . CardiacNT-proBNP concentrations were determined with an immunoradiometric assay kit . Normal values are depending on age and gender, but in general a NT-proBNP <200 pg/ml is considered normal. Cardiac troponin T concentrations were determined using a microparticle enzyme immunoassay . A normal value was considered a troponin T <0.04 ng/ml.U) was performed.All analyses were performed using the SPSS statistical software package . Data are shown as mean ± SD or median (range). Biochemical parameters were log-transformed before analysis. The Student-t test was used to compare RV parameters between treatment arms and to compare relative change of RVED compared to baseline between treatment arms. Students-t test was chosen primarily to calculate confidence intervals which may be appropriate for power analysis for future studies. Moreover, due to small sample sizes and non-normal distributions of biochemical parameters, also a nonparametric test  or placebo . After 24 hours, RVED had increased by 2.4% in the placebo arm and had decreased by 5.6% in the epoprostenol arm ). Results were similar for the 3 patients in whom epoprostenol was titrated to a mean dose of 7.2 ng/kg/min (data not shown).At baseline, the mean RVED was similar in both treatment groups (4.10 ± 0.83 cm in the epoprostenol arm and 4.13 ± 0.84 cm in the placebo arm). Epoprostenol did not have a significant effect on RVED after 2.5 and 24 hours . Systolic PAP at baseline and follow up for both treatment groups is presented in Figure Measurements of systolic PAP, TAPSE, RVFAC, end-diastolic right atrial diameter, end-diastolic right/left ventricular ratio and biochemical parameters of right ventricular overload are presented in Table 2, PaCO2 or SaO2) were similar at baseline and did not significantly change during treatment (data not shown). There were no blood pressure changes necessitating fluid resuscitation or lowering of the epoprostenol infusion rate.There were no serious adverse events in either treatment arm. Two patients showed facial flushing during infusion with epoprostenol, however, this was transient and did not influence infusion rate. As described above, in one patient administraton of epoprostenol could not be increased to a maximum 8 ng/kg/min because of persistent facial flushing and headache. Symptoms disappeared after gradual lowering of the infusion rate. Parameters of pulmonary gas exchange  in the setting of right ventricular dilatation in acute pulmonary embolism . Three sWhy doesn't epoprostenol have a more pronounced effect? In animal models of acute pulmonary embolism, treatment with different vasodilators, including prostacyclin, was associated with a more pronounced decrease in mean PAP of 12-33% ,25-27. H2 (data not shown) did not occur in the patients who received epoprostenol infusion in our study. Inhalation of prostacyclin or nitric oxide is more selective for pulmonary vasculature and has shown to decrease pulmonary artery pressure in case reports of acute pulmonary embolism [The choice for intravenous epoprostenol as a vasodilator merits discussion. Firstly, it could be argued that intravenous administration of epoprostenol might cause nonselective vasodilation which could lead to intrapulmonary shunting and systemic hypotension. However, hypotension or a decrease in POembolism ,31. Howeembolism  and inhaembolism , yet a rembolism . In humaembolism ,36. The embolism . FinallyThis small randomized controlled trial investigated the effect of epoprostenol in patients with acute pulmonary embolism and right ventricular dilatation. In contrast to the results of several case reports and studies in animals, treatment with epoprostenol in humans did not improve right ventricular dilatation or any other measured variables of right ventricular overload.Albertus J Kooter has no conflicts of interest to disclose; Richard G IJzerman has no conflicts of interest to disclose; Otto Kamp has no conflicts of interest to disclose; Anco B Boonstra's employer received in the past 3 years an unrestricted educational grant from GSK and Actelion, and has been reimbursed for doing phase III trials for GSK and Actelion. Anco Boonstra has served as a paid speaker for Actelion; Yvo M Smulders has no conflicts of interest to disclose.AJK was involved with data acquisition, participated in the design of the study, performed the statistical analysis and drafted the manuscript; RGIJ participated in the statistical analysis and manuscript drafting; OK carried out the echocardiographic analysis; ABB participated in the design of the study; YSM supervised the design of the study, participated in the statistical analysis and manuscript drafting. All authors read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/10/18/prepub


Pulmonary edema after device closure of atrial septal defect (ASD) is a rare complication. We present illustrative images of a case of pulmonary edema after device closure of ASD in a 53 year old adult. Older patients undergoing ASD closure can benefit from their left atrial and left ventricular end diastolic pressures measurement before and after temporary balloon occlusion of ASD. These images illustrate the development of pulmonary edema after catheter closure of atrial septal defect (ASD) in a 53-year-old gentleman. He presented with shortness of breath and easy fatigability since six months. He was normotensive and non-diabetic with no history of effort angina. The chest X-ray obtained before the procedure  showed cEighteen hours after device closure the patient developed breathing difficulty and orthopnea. Clinical examination showed tachypnea and basal crepitation. Skiagram of chest in postero-anterior view showed features of evolving pulmonary edema  which eset al.[et al. reported pulmonary edema in a 78-year-old male. Our patient was relatively younger (53 years) without any coronary artery disease and normal systemic pressure.ASD is a common form of congenital heart disease accounting for approximately 10% of all congenital cardiac defects.[et al. reportedIn older patients, an impaired diastolic ventricular function due to reduced ventricular compliance is observed more frequently although this is occasionally also seen in childhood. RestrictOlder patients undergoing ASD closure in the catheterization laboratory should perhaps have their left atrial, LVEDP measured before and after temporary balloon occlusion and after defect is closed with a device.