A subset of children and adults with Wolff-Parkinson-White (WPW) syndrome develop dilated cardiomyopathy (DCM). Although DCM may occur in symptomatic WPW patients with sustained tachyarrhythmias, emerging evidence suggests that significant left ventricular dysfunction may arise in WPW in the absence of incessant tachyarrhythmias. An invariable electrophysiological feature in this non-tachyarrhythmia type of DCM is the presence of a right-sided septal or paraseptal accessory pathway. It is thought that premature ventricular activation over these accessory pathways induces septal wall motion abnormalities and ventricular dyssynchrony. LV dyssynchrony induces cellular and structural ventricular remodelling, which may have detrimental effects on cardiac performance. This review summarizes recent evidence for development of DCM in asymptomatic patients with WPW, discusses its pathogenesis, clinical presentation, management and treatment. The prognosis of accessory pathway-induced DCM is excellent. LV dysfunction reverses following catheter ablation of the accessory pathway, suggesting an association between DCM and ventricular preexcitation. Accessory pathway-induced DCM should be suspected in all patients presenting with heart failure and overt ventricular preexcitation, in whom no cause for their DCM can be found. Clinically relevant arrhythmias are frequently encountered in patients with Wolff-Parkinson-White (WPW) syndrome  . ReentraTwo invariable clinical features associated with this type of DCM are: 1) absence of recurrent and sustained tachyarrhythmias ("asymptomatic" WPW), and 2) presence of right-sided accessory pathways, with overt ventricular preexcitation on 12-lead surface electrocardiogram (ECG) -12. It iThe exact prevalence of DCM and LV dysfunction in patients with asymptomatic WPW is unknown. Only 27 cases of accessory pathway-induced DCM have been reported thus far . The cliLV dysfunction has been described in more than 50% of patients with right-sided septal accessory pathways ,9. AlthoAt present, the pathogenic mechanism for the development of LV dysfunction and DCM in patients with asymptomatic WPW has not yet been fully elucidated. Interestingly, a right-sided septal or paraseptal accessory pathway has been documented in all patients with overt ventricular preexcitation who developed LV dysfunction or DCM in the absence of recurrent tachyarrhythmias  -12. ThisWPW is a disorder of normal cardiac conduction. It is characterized electrocardiographically by presystolic depolarization and contraction of a part of the ventricular myocardium via an accessory pathway. The effects of premature ventricular activation on cardiac wall motion and global ventricular function has intrigued cardiologists  -17. AtteLeft-sided accessory pathways may produce a typical premature anterior motion of the LV posterior wall, which can be identified on M-mode echocardiography as a small, distinct bump in early systole of the LV posterior wall . On the Recently, several investigators have demonstrated reduced systolic LV function in patients with right- sided septal and paraseptal accessory pathways ,9. A lowAn important clinical finding is that cardiac function improves and normalizes in patients with LV dysfunction or DCM, following loss of ventricular preexcitation, either spontaneously or due to cardiac catheter ablation or medical therapy -12. MoreSeptal accessory pathway-induced ventricular dyssynchrony is an important feature in the development of LV dysfunction and DCM ,7,9. We As timing is crucial for synchronous ventricular contraction and regional myocardial function, a delay in electrical activation of a myocardial segment, due to left bundle branch block (LBBB), right ventricular apical pacing, or chronic heart failure, may contribute to cardiac pump inefficiency -25. UsinTwo recent studies used conventional echocardiographic and speckle tracking imaging methods to quantify LV dyssynchrony in patients with WPW and septal accessory pathways ,9. Pre-aHowever, not all patients with ventricular preexcitation and right-sided accessory pathways seem to be at risk for developing severe LV dysfunction or DCM. Possibly, the degree of pathway-induced LV dyssynchrony is an additional risk factor in these patients. Recent work suggests that different types of septal accessory pathways may induce a variable degree of LV dyssynchrony -7,9. IntAs with all forms of heart failure and DCM in pediatric and adult patients, the underlying diagnosis must be considered. All patients should undergo standard electrocardiographic and echocardiographic assessment. Although there are certain age-related differences in the diagnostic work-up, the approach has to be individualized, depending on clinical findings, age and family history. A comprehensive summary of various important aspects in the diagnostic work-up of patients presenting with DCM have been well reviewed elsewhere ,27. In gThe prognosis of right-sided accessory pathway-induced DCM is excellent, when the diagnosis is suspected early in the clinical course and appropriate therapy is initiated -12. The Although catheter ablation is now considered as the standard therapy in adults and children > 12 kg with tachyarrhythmias , it may Many asymptomatic patients with WPW and septal accessory pathways have LV dysfunction ,9. The eAnother interesting aspect in the clinical management of patients with WPW and LV dysfunction is whether QRS duration can be used for assessment of degree of ventricular dyssynchrony. Recent reports have shown an increased QRS duration in patients with septal and paraseptal accessory pathways ,9. HowevAccessory pathway-induced DCM is a newly recognized form of LV dysfunction in asymptomatic WPW patients with right-sided pathways, in the absence of incessant tachyarrhythmias. Right-sided accessory pathways mediate ventricular dyssynchrony, inducing adverse remodelling and DCM. With loss of ventricular preexcitation, either spontaneously or after catheter ablation, LV function reverses completely. The prognosis of accessory pathway-induced DCM is excellent.


Arrhythmogenic right ventricular dysplasia (ARVD) is a genetic cardiomyopathy characterized clinically by ventricular arrhythmias and progressive right ventricular (RV) dysfunction. The histopathologic hallmark is fibro-fatty replacement of RV myocardium. It is inherited in an autosomal pattern with variable penetrance. ARVD is unique in that it most commonly presents in young, otherwise healthy and highly athletic individuals. The cause of ARVD is not well-known but recent evidence suggests strongly that it is a disease of desmosomal dysfunction. The disease involvement is not limited only to the RV as left ventricle (LV) has also been reportedly affected. Diagnosis of ARVD is challenging and is currently based upon a multi-disciplinary work-up of the patient as defined by the Task Force. Currently, implanted cardioverter defibrillators (ICD) are routinely used to prevent sudden death in patients with ARVD. Cardiovascular MR is an important non-invasive diagnostic modality that allows both qualitative and quantitative evaluation of RV. This article reviews the genetics of ARVD, current status and role of CMR in the diagnosis of ARVD and LV involvement in ARVD. Arrhythmogenic right ventricular dysplasia (ARVD) is a progressive cardiomyopathy primarily affecting the right ventricle (RV) and is characterized by fatty/fibro-fatty replacement with myocyte loss, ventricular arrhythmias of left bundle branch block pattern (LBBB) and right heart failure. Increasing evidence suggests that ARVD is a disease of desmosomal dysfunction. ARVD can exist in both sporadic and familial forms with the familial form showing a predominantly autosomal dominant inheritance pattern with variable penetrance. The exact prevalence is unknown, but it is estimated to be 1:5000 in the United States. The clinical onset of ARVD is often delayed to adolescence or early adulthood. It is more commonly seen in males and people engaged in athletics and competitive sports.ARVD accounts for up to 5% of sudden deaths in young individuals less than 35 years of age in the United States, and 25% of exercise-related deaths in Veneto, Italy ,2. The dThe diagnosis of ARVD is based upon a set of major and minor criteria proposed by the Task Force of cardiomyopathies in 1994 . The diaImportant morphological patterns of ARVD manifestation include myocyte loss with fibro-fatty replacement of the ventricular myocardium, focal thinning of ventricular free wall, wall hypertrophy, focal bulging of the RV wall in diastole and RVOT enlargement. Functionally, the disease may result in global or regional contraction abnormalities, RV systolic/diastolic dysfunction, RV dilatation and RV aneurysms. The imaging modalities used for RV assessment in ARVD include conventional angiography, echocardiography, radionuclide angiography, computed tomography (CT) and cardiovascular magnetic resonance (CMR). The standard of reference for the diagnosis of ARVD has been the histo-pathological demonstration of fibro-fatty replacement of the RV myocardium at either surgery or autopsy. Unfortunately biopsy carries risk of perforation and has low sensitivity on account of the segmental nature of fatty infiltration. The major therapeutic decision involved in the care of a patient with ARVD involves the decision to implant an implantable cardioverter defibrillator (ICD). Anti-arrhythmic drug therapy and catheter ablation may be useful to decrease the frequency of sustained ventricular arrhythmias and ICD firing. In case of intractable RV failure or incessant ventricular arrhythmias which are refractory to anti-arrhythmic drug therapy and/or catheter ablation, cardiac transplantation may be an option for treating patients with ARVD.As novel mutations in desmosomal proteins are being reported, the relationships between genetic mutation and phenotypic expression are beginning to be understood, particularly in the context of CMR diagnosis. This review discusses these relationships and the role of CMR for evaluation of patients with ARVD.ARVD is known to occur in both sporadic and familial forms, with familial disease accounting for an estimated 30% to 80% cases . FamiliaTo date, seven genes have been implicated in the dominant and recessive ARVD, including transforming growth factor- β3 (TGFβ3) in ARVD1 , cardiacARVD shows polymorphic expressivity with variable clinical expression of PKP2 mutations even among first-degree relatives ranging from a complete lack of symptoms to a severe disease phenotype experiencing sudden cardiac death (SCD)/right or biventricular heart failure. This large heterogeneity in clinical expression can be attributed to factors such as involvement of different desmosomal genes, different mutations within the same gene and effect-modification by other genetic and environmental factors. Dominant ARVD due to PKP2 mutations has also widely been shown to have an age-dependent, variable penetrance which could again be attributed to modifier genes, environmental influences and gender effects -29. In cThe genetic patterns of ARVD are complex, with heterogeneity in causative genetic mutations and abnormality within the same gene showing varied patterns of inheritance and phenotypic expression and vice versa. Mutations in DSP have been shown to underlie autosomal dominant and recessive skin disorders, with or without cardiac involvement . Awad etIdentification of causative desmosomal mutations has resulted in ARVD to be increasingly viewed upon as a desmosomal disease and has provided insight into its pathogenesis. Mutations affecting components of the cardiac desmosome are believed to disrupt cell-cell adhesion, provoking detachment of myocytes particularly under conditions of mechanical stress. This, in turn, might lead to apoptosis and cell necrosis, predisposing to inflammation and repair by fibro fatty substitution.Accordingly, early ARVD shows predilection for the regions of heart with relatively thinner walls and high shear stress – the subtricuspid portion, outflow tract, apex and mid-free wall of the RV ("triangle of dysplasia") and the inferior wall septal junction and infero-lateral wall of the LV. Young individuals and athletes are predisposed because of high level of physical activity and resultant greater strain on heart. Gap junction remodeling associated with impaired mechanical coupling at cell adhesion junctions may result in a predisposition to the arrhythmogenicity seen in ARVD. Furthermore, adrenergic stimulation during highly strenuous activity may precipitate arrhythmic events in patients with ARVD. Desmosomal mutations may induce nuclear protein dysfunction as desmosomal proteins are believed to be involved in regulation of transcription. Desmosomal mutations may also heighten the pathogenic role of viral infection speculated in the causation of ARVD ,36,37.A pathogenic role of cytoplasmic calcium overload is shown by the association of mutations in RYR2 with ARVD2. This type of ARVD has a very different clinical presentation and is rather distinct from the more common types of ARVD. RYR2 has also been independently implicated in isolated familial catecholaminergic polymorphic VT (CPVT) reflecting possibly different mutations within the same gene and the probable role of effect-modification by individual genetic make-ups and environmental influences in different phenotypic expressions of the same genetic abnormality . Finally2 and V3  . Signal Cardiac-gated spin-echo (SE) pulse sequences have conventionally been used for evaluation of cardiac morphology. CMR black-blood techniques have been developed for cardiovascular imaging to improve segmentation of myocardium from the blood pool. Black blood in the cardiac chambers is achieved by saturation of inflowing blood signal both above and below the acquired volume.Current black blood CMR techniques Figure  use a brBlack-blood single shot fast SE sequences employ 180 degrees radiofrequency re-focalization pulses preceded by an inversion double pulse associated to pre-saturation pulses. Although these methods substantially reduce motion artifacts and imaging time, the single shot approach frequently results in loss of visualization of the RV. Thus single shot SE is not recommended unless severe arrhythmia is present resulting in failure of other black blood sequences. A full CMR protocol for ARVD is shown in Table Sensitivity and specificity of CMR detection of RV intra-myocardial fat in diagnosis of ARVD is variable, ranging from 22% to 100% ,52,54,62Castillo et al  demonstrThe varying sensitivities that have been reported for CMR to detect intra-myocardial fat can be ascribed to patient selection, which includes not only those with overt forms of the disease with extensive morpho-functional alterations and inducible arrhythmias, but also those with concealed forms without global dysfunction and without inducible arrhythmias . IsolateThe reliability of detecting increased intra-myocardial T1 signal is probably low. Bluemke et al  reportedAbbara at al  reportedBy the application of CMR, Harper et al  confirmeLate-enhancement (LE) CMR has the potential to identify myocardial fibro-fatty changes in both RV and LV in ARVD ,67. CMR A potential role of CMR lies in its ability to detect early and subtle cases of ARVD which are otherwise insensitive to diagnosis by Task Force criteria, posing a real diagnostic dilemma. In patients with structurally severe disease, all imaging modalities are likely to provide abnormal findings and the ability of CMR to do so therefore does not stand out . CMR canRegional functional abnormalities of RV in ARVD include focal hypokinesis , akinesis , dyskinesis , and aneurysms (segments with persistent bulging in diastole and dyskinetic in systole) . MyocardRegional functional abnormalities have been shown to correlate with areas of signal abnormality. The presence of regional abnormal wall motion associated with signal abnormality is more suggestive of ARVD than either of them alone . AbnormaMR imaging is a useful tool in the evaluation of patients with suspected ARVD. However, it is important to recognize that CMR is not a "gold standard" for the diagnosis of ARVD. But rather, CMR is one of a number of tests which should be employed in the evaluation of patients with suspected ARVD. Other tests which should be performed include a 12 lead electrocardiogram (ECG), signal-averaged ECG (SAECG), Holter monitor, stress test, and echocardiogram. If these tests suggest ARVD, we at our institution, typically recommend biopsy to confirm the diagnosis and exclude other potential etiologies (such as sarcoidosis) mainly in sporadic cases as well as EP study as a part of risk stratification . Great cCurrently, two large clinical trials are under-way that use CMR for ARVD diagnosis. The European ARVD registry  attemptsLV involvement in ARVD has been increasingly described, with prevalence reported as 16%  to 76% . Hebert Lindstrom et al  demonstrThese cases of early and/or predominant LV involvement in ARVD have brought into question the traditional consideration of LV involvement as only an end-stage complication of progressive RV dilatation and dysfunction in ARVD. Although there is not a complete agreement in literature, LV involvement in ARVD may not stand for a separate disorder, but may be part of a larger disease process extending across the entire heart supporting the adoption of a broader term "arrhythmogenic cardiomyopathy" with appropriate sub-classifications .The most common variant of ARVD has been postulated to be biventricular with LV involvement from its early stages. The rationale for this is the classification of ARVD as a desmosomal disease and desmosomal genes are expressed in both ventricles. Desmosomal mutations that primarily affect cell adhesion may affect the distensible, thin-walled RV earlier in the course of the disease. LV dysfunction in ARVD may also be secondary to the enlarged and poorly functioning RV because physiologically heart cannot be compartmentalized into functionally independent right and left sides.LV involvement in classic ARVD is characterized by extension of T-wave inversion in the ECG lateral leads , arrhythmia of LV or biventricular origin, and/or isolated LV dilatation and impairment . ARVD faFibro-fatty replacement of the LV shows correlation with myocardial perfusion defects predominantly located in antero-septal and basal posterior segments of the LV, adjacent to the parts of the RV most frequently affected by the disease . Other qLV involvement in ARVD appears histologically similar to the RV findings or is only fibrotic . PinamonWhen Task Force criteria were first proposed, minimal LV disease was a stipulation, intended to improve specificity of a then little known disease and ensure distinction from related disorders such as dilated cardiomyopathy. It appears likely that descriptions of LV involvement may be included in subsequent revisions of the diagnostic criteria for ARVD .ARVD presents a diagnostic challenge on account of the inherent difficulty in its diagnosis using conventional methods, lack of clinical experience due to the rare nature of disease and high frequency of misdiagnosis of the condition. Also, there is no gold standard for its diagnosis and the Task Force criteria which are currently relied upon have never been validated. CMR plays an important role in the diagnosis of ARVD that is both qualitative and quantitative. The recent expansion of the genetic understanding for ARVD will underscore the importance of noninvasive imaging techniques for early phenotypic characterization of this disorder.ARVD: arrhythmogenic right ventricular dysplasia; AV: atrioventricular; CMR: cardiovascular magnetic resonance; ECG: electrocardiogram; EF: ejection fraction; ETL: echo train length; FOV: field of view; FSE: fast spin echo; GRE: gradient echo; ICD: implantable cardioverter defibrillator; LBBB: left bundle branch block; LE: late enhancement; LV: left ventricle; RV: right ventricle; RVFWT: right ventricle free wall thickness; RVOT: right ventricular outflow tract; SCD: sudden cardiac death; SE: spin echo; SSFP: steady state free precession; TE: echo time; TI: inversion time; TR: repetition time; TSE: turbo spin echo; WMA: wall motion abnormalityThe authors declare that they have no competing interests.AJ and HT drafted the initial review article, AJ performed the literature search, HC and DB participated in the article organization, editing and final drafting of the manuscript. All authors read and approved the final manuscript.


To compare the accuracy of simplified 3-dimensional (3-D) echocardiography vs. multi-slice computed tomography (MSCT) software for the quantification of left ventricular (LV) volumes.Three-D echocardiography (3-planes approach) and MSCT-CardIQ software were calibrated by measuring known volumes of 10 phantoms designed to closely mimic blood-endocardium interface. Subsequently, LV volumes were measured with both the methods in 9 patients referred routinely for coronary angiography and the agreement between the measurements was evaluated.Simplified 3D-echocardiography provided higher degree of agreement between the measured and true phantom volumes  than MSCT software . The agreement between LV measurements in the patients was considerably poorer, with significantly larger volumes produced by MSCT .Simplified 3-D echocardiography provides more accurate assessment of phantom volumes than MSCT-CardIQ software. The discrepancy between the results of LV measurements with the two methods is even greater and does not warrant their interchangeable diagnostic use. Echocardiography and x-ray based computed tomography provides possibilities of detailed evaluation of cardiac morphology and function and the introduction of these techniques constitutes without any doubt an important landmark in the history of diagnostic cardiology. Today, both the methods not only form a backbone of diagnostic cardiac procedures but also are much appreciated as sensitive research instruments. Recently, the diagnostic capacity of echocardiography has been further improved by the addition of 3-dimensional cardiac imaging.An important link in the process of cardiac diagnostics is accurate estimation of left ventricular volume. In this respect, MSCT has been shown to be both feasible and accurate when compared with left ventriculography , magnetiin vitro setting using phantoms.However, the results of a recently published study indicate that even though both 3-D echocardiography and MSCT measurements correlate highly with magnetic resonance imaging, 3-D echocardiography compares more favourably in this respect than MSCT that tend to overestimate the magnetic resonance values . TherefoTen different cone-shaped phantoms were used in the study. Eight of them were manufactured with a symmetric geometric structure and two with asymmetric geometry that was considered to mimic LV with an aneurysm. All the phantoms were manufactured using water-based microbiology agar  described by Burlew et al. . In ordeThe speed of ultrasound in the phantom material was measured in two pieces of the phantom material, one with and the other without glass powder, using piezoelectric crystals (one working as a transmitter and the other as a receiver) applied to the opposite sides of the test pieces. An electrical circuit and an oscilloscope connected to the crystals measured the time for a pulse of ultrasound to travel the distance between the crystals. The velocities of ultrasound within the phantoms were found to be 1470 m/s in the outer section with the glass powder and 1540 m/s in the inner section with iodixanol.Nine patients (5 men), aged 64 (range 51–82) years were selected consecutively from a larger, prospective study evaluating efficiency of coronary MSCT for the detection of coronary artery disease in patients referred routinely for coronary angiography due to known or suspected coronary artery or valvular diseases. In all the selected patients, 3-D echocardiography was performed in addition to MSCT. Both 3-D echocardiography and MSCT data were evaluated by independent trained interpreters. The study was approved by the local ethics committee of Karolinska University Hospital, Stockholm, Sweden.The echocardiographic study was performed using a GE Vingmed Vivid 7 equipment and V3 matrix transducer allowing simultaneous acquisition of image data in 3 different planes positioned at 60° angle to each other. In each of the 10 phantoms, the acquisition of echocardiographic data for the subsequent volume measurements was performed five times by placing the transducer close to the basal plane of the respective phantom submerged in water. In the patients, cineloops of 3 consecutive cardiac cycles were acquired at end-expiration from transthoracic apical window with a sampling frequency of 30 frames/s. The respective data sets were subsequently stored for offline analysis using a GE Echopac workstation and the Echopac software version BT06. In each of the three images generated simultaneously in three different planes by V3 Matrix transducer, the geometry and the area corresponding to LV cavity or to the inner section of the phantom  LightSpeed VCT, Milwaukee, Wisc., USA). The gantry rotation time was 0.35 seconds, while a collimation of 64 × 0.625 mm and a tube voltage of 120 kV was used. In the patients, dose modulation was used and the tube current was diminished during systole resulting in the effective current of approximately 240–640 mAs and effective dose of 20.0 mSv. All images (both in patients and phantoms) were acquired with slice thickness of 5 millimetres and spacing equal to 4 millimetres. A bolus injection of 85 ml iodixanol  was given intravenously to the patients at a rate of 4–6 ml/sec followed by a flush with 50 ml of saline. Using retrospective electrocardiographic gating, reconstruction of images from 10 phases of the cardiac cycle was done for the patients.The patient and phantom CT data sets were subsequently transferred to a dedicated workstation  for further processing using GE CardIQ Function Version 1.0.3 software. Volumes of the phantoms and the left ventricles were evaluated using this semi-automated software. Data sets consisting of 5 mm thick axial images were loaded into the CardIQ software. For the patients, the images were reconstructed with retrospective ECG gating at 10% R-R interval increments throughout the cardiac cycle. The diastolic volume was determined at 0% of the R-R interval and the systolic volume at 40% of the R-R interval. Short-axis images were reconstructed and automatic contour detection of the inner-volume of the phantoms and the myocardial border in left ventricle was performed Fig. . Minor mt-test. The data are presented as mean ± SD unless otherwise stated.Univariate relations between echocardiographic and MSCT-CardIQ measured LV volumes as well as their relation to the true phantom volumes were tested with standard regression analysis. Assessment of agreement between 3-D echocardiography and MSCT-CardIQ software in volume measurements was performed using the method of Bland and Altman . Paired 2 = 1.00; y = 0.51 + 1.00x) and MSCT-CardIQ software . However, the results obtained with the two methods differed (p < 0.001). The true phantom volumes and the average volumes based on five volume measurements in each phantom with each method are presented in Table The used MSCT CardIQ software provided fully adequate delineation of the inner section of the symmetric phantoms Fig. , right bThe poor agreement between 3-D echocardiography and MSCT-CardIQ software is further illustrated in Bland-Altman plot in Figure 2 = 0.62 (y = -10.99 + 1.19x) for the end-systolic, and r2 = 0.59 (y = 32.39 + 0.91x) for the end-diastolic volume. Similar to what was observed in the phantom experiments, the results produced by the two tested methods . This was a seed growing software that instead of outlining the endocardial border, worked by binding voxels with similar Hounsfield values assumed to originate from the same sort of tissue. Since the software did not work satisfactorily in phantoms, only measurements of LV volumes in patients were performed. The results are presented in Bland-Altman plot in Figure In this context, it should be remembered that beside the currently reported results of volume measurements, there are other important factors that would favour the diagnostic use of 3-D echocardiography. For example, the effective radiation dose associated with the MSCT procedure employed in the present study was 20.0 mSv that is a dose equivalent to 1000 chest x-rays or nearly 7 years of background radiation . On the The present results demonstrate that simplified 3-D echocardiography provides a reliable and significantly more accurate assessment of phantom volumes than MSCT-CardIQ software. The discrepancy between the results of both methods increase considerably when LV volume is measured and the limits of agreement are not acceptable for interchangeable diagnostic use of the both methods. Judging from its performance on phantoms, simplified 3-D echocardiography can be expected to provide most accurate LV volume assessments in clinical situations.The authors declare that they have no competing interests.MM constructed the phantoms, performed phantom volume measurements with 3-D echo and MSCT, and prepared the manuscript. RW performed the 3-D echo examination and LV volume calculation on patients. KC, JR and HMA performed MSCT examinations on both phantoms and patients. They performed volume calculations in patients with both software and participated in the manuscript preparation. JN performed statistical analysis and was responsible for the final layout of the manuscript. LÅB initiated and supervised the study and participated in the manuscript preparation. All authors read and approved the manuscript.


Hypertrophic cardiomyopathy (HCM) is an extremely heterogeneous disease. An under recognized and very often missed subgroup within this broad spectrum concerns patients with left ventricular (LV) apical aneurysms in the absence of coronary artery disease.We describe a case of HCM with midventricular obstruction and apical aneurysm formation in 3 patients coming from a single family. This HCM pattern was detected by 2D-echocardiography and confirmed by cardiac magnetic resonance imaging. A cardioverter defibrillator was implanted in one of the patients because of non-sustained ventricular tachycardia detected in 24-h Holter monitoring and an abrupt drop in systolic blood pressure during maximal exercise test. The defibrillator activated 8 months after implantation by suppression of a ventricular tachycardia providing anti-tachycardia pacing. The patient died due to refractory heart failure 2 years after initial evaluation. The rest of the patients are stable after a 2.5-y follow-up period.The detection of apical aneurysm by echocardiography in HCM patients may be complicated. Ventricular tachycardia arising from the scarred aneurysm wall may often occur predisposing to sudden death. Hypertrophic cardiomyopathy (HCM) is an extremely heterogeneous disease, in terms of clinical course and phenotypic expression -3. An unWe studied 3 female patients  (Figure In this report we present a case of HCM with midventricular obstruction and apical aneurysm formation in 3 patients coming from a single family.Isolated midventricular obstruction is an uncommon phenotype of HCM ,11. The The detection of apical aneurysms by echocardiography in HCM patients may be complex, if hypertrophy is confined to posterior septum, LV free wall, or to the apex. Furthermore, echocardiographist's experience, the quality of acoustic window and acquired images along with aneurysm's size play an important role in the aneurysm identification. According to a previous study, echocardiography identified only 57% of HCM patients having aneurysms, all of which were either medium or large .The mechanism responsible for the formation of apical aneurysms in HCM patients remains unresolved while several causes have been accused, such as increased LV wall stress as a result of midcavitary LV obstruction and elevated intracavitary systolic pressures, genetic predisposition and myocardial bridging of the left anterior descending coronary artery .The formation of apical aneurysm in HCM represents a very serious clinical form of the disease. Very often, LV systolic function is depressed and thrombi may be developed inside the aneurysm leading to embolic events. Ventricular tachycardia arising from the scarred apical wall may also occur, predisposing to sudden death.LV apical aneurysms affect up to 2% of the entire HCM population. Their detection using 2D echocardiography may be difficult. MRI imaging, on the contrary, shows 100% sensitivity in revealing them. The presentation of apical aneurysms in HCM patients is connected to serious complications including embolic events or even sudden death.Written informed consent was obtained at first visit from all patients for publication of this case report and all accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.GKE and EP conceived the case report, collected the data, reviewed literature and wrote the manuscript. IHS and GP revised the article for important intellectual content and edited the final version. GKE, DGP and CP performed the ultrasounds and participated in the analysis and interpretation of data. GS performed cardiac MRI. SP implanted the ICD. All authors read and approved the final manuscript.Transthoracic echocardiography movie. This movies shows an apical two chamber view during 3 cardiac circles demonstrating mid-ventricular septal and lateral walls thickening and apical aneurysm formation in case-index 1 patient.Click here for fileCardiac Magnetic Resonance movie. Cardiac MRI movie obtained from case index-2 patient showing systolic midventricular wall thickening and an apical aneurysm.Click here for fileCatheterization movie. Catheterization movie revealing systolic left midventricular obstruction and apical aneurysm in case-index 2 patient.Click here for file


Pulmonary hypertension due to delay in presentation, diagnosis, referral, and surgery for septal defects is not uncommon in the developing world and translates into high morbidity and mortality following open heart surgery to close these defects. Leaving a small atrial communication may not always be effective. Extracorporeal membrane oxygenation and inhaled nitric oxide therapy in the immediate postoperative phase may not be available or may not be financially feasible in many institutions which are economically challenged. Unidirectional valved patch is emerging as a new and effective solution to this problem and promises to make at least the immediate postoperative results more predictable in this subset of patients. In developing countries, it is not uncommon to encounter patients with ventricular and atrial septal defects who present beyond infancy.2 These pA common surgical strategy to improve outcome in these patients consists of leaving behind a small interatrial communication to provide a pop-off during periods of elevated right-sided pressures when the resultant right-to-left shunt through the interatrial communication prevents acute right ventricular failure at the cost of systemic desaturation. The degree of shunting through this communication is unpredictable, and rarely some of these may require percutaneous intervention to close this communication if the pulmonary artery pressures subside and a left-to-right shunt ensues. A fenestration in the patch used to close the defect with a valved mechanism can potentially serve as a pop-off in one direction at the level of the previous shunt . When the left-sided pressures exceed right-sided pressures, the valve closes and prevents a left-to-right shunt.A variety of techniques have been utilized for creating a unidirectional valved patch (UVP).–21 The pet al., TheWe have developed a simplified technique at our institution to address the limitations posed by other techniques. This technique is described in detail elsewhere. After inµg/kg/min, nitroglycerin or nitroprusside 0.5–2 µg/kg/min, or the phosphodiesterase inhibitor milrinone prior to discontinuation of CPB. Some advocate placing transthoracic pulmonary artery catheters in all patients to monitor pulmonary artery pressures in the postoperative phase. Intraoperative transesophageal echocardiography and postoperative transthoracic echocardiography is used to assess the result of the operation and the degree of shunting across the fenestration. After termination of CPB, moderate hypocarbia is commonly employed in the operating room. Once the patients are fully awake and hemodynamically stable, they are extubated. Upon resuming oral intake, oral angiotensin converting enzyme inhibitor or phenoxybenzamine is started and the inotropes are weaned off. Sildenafil may be administered depending upon the institutional protocol. Anticoagulants/aspirin are not administered.It has been our practice to start dopamine 5–10 2 using pulse oximetry and trans-thoracic echocardiography at regular intervals to estimate the pulmonary artery (PA) pressure, assess the right ventricular function and demonstrate the degree of right-to-left shunting. Cardiac catheterization is usually not indiacted.After discharge from the hospital, follow-up consists of clinical examination measurement of SpOThe results obtained with the use of UVP by various groups are summarized in . Two deaAll the described techniques have their advantages and disadvantages. It is difficult to compare the results of various techniques because of small numbers and heterogeneity of the patient population. These series have included a wide range of patients with diagnosis such as VSD, ASD, AVSD, double outlet right ventricle, total anomalous pulmonary venous drainage, etc. The overall results observed in these series have been gratifying. However, all the earlier techniques have been found to be time consuming. The UVP in these techniques is always constructed after cardioplegic arrest and assessment of the defect as fashioning the patch prior to this may result in improper sizing of the patch. Also, two patches are often required to construct the UVP, a procedure which adds to the ischemia time. In the original description by Novick, one patient died due to left ventricular outflow tract obstruction due to the movement of the patch necessitating a further modification whereby the valve was placed toward the apex of the left ventricle. The technique described by Zhang is innov2 before and after surgery, and response to exercise with demonstration of the direction of shunt through the patch using contrast echocardiography may potentially answer questions about the long-tem usefulness and integrity of the valve mechanism. Cardiac catheterization with detailed hemodynamic evaluation can be performed if the patients consent to undergo this procedure.Unfortunately, in the absence of a randomized study with controls, it is not possible to conclusively demonstrate that a UVP can actually reduce the mortality and improve survival. The magnitude of right-to-left shunt has not been quantified in any of these studies. Prospective studies with a detailed evaluation and description of the patients’ resting POThe UVP is designed only to tide over the period of hemodynamic instability in patients with septal defects and severe PAH and to provide a safe closure of the septal defects in patients with "border-line operability". Given the present day indications, this approach helps to salvage these patients in the short to mid-term but the long-term effects of this technique on the natural history of patients with long standing severe PAH are unknown. We have no data to support the use of this technique in patients with established Eisenmenger's syndrome.


Pulmonary arterial hypertension (PAH) in patients with systemic sclerosis is associated with a poor prognosis, but this can be improved by early disease detection. Abnormal pulmonary and cardiac function can be detected early by means of echocardiography, whereas right heart catheterization is usually performed later.The purpose of this prospective study was to detect early the presence of pulmonary artery vasculopathy in patients with verified systemic sclerosis without significant pulmonary fibrosis, normal lung volumes and a mildly reduced lung diffusion capacity of carbon monoxide (DLCO).2). They all underwent complete Doppler echocardiography, CPET, a pulmonary ventilation test , HRCT. To investigate PAH by means of complete resting Doppler echocardiography estimates of systolic pulmonary artery pressure (PAPs) derived from tr icuspid regurgitation, mean PAP derived from pulmonary regurgitation, pulmonary vessel resistance (PVR) derived from the acceleration time of the pulmonary outflow tract (ACTpo), and right ventricular function derived from tricuspid annular plane systolic excursion (TAPSE). Right heart catheterisation was conducted only, if pulmonary hypertension was suggested by echocardiography and an abnormal ventilator test.Nineteen consecutive female NYHA class I-II patients with scleroderma and a PAPs of < 35 mm/Hg measured by echocardiography, were enrolled between September 2007 and September 2009. They had a mean age of 51 ± 13 years, body mass index of 25 ± 5 kg/mr coefficient, and the predictive value of the variables was calculated using linear regression analysis. A p value of > 0.05 was considered significant.The data are given as mean values ± SD, unless otherwise stated. The correlations between the variables were analysed using Pearson's Right heart catheterization detected PAH in 15/19 patients; mean PAP was 30.5 mm/Hg and RVP 3.6 UW. Coronary angiography of the patients aged more than 55 years showed some evidence of significant coronary artery disease. Echocardiography showed high systolic PAP values (46 ± 8 mmHg), whereas right ventricular function was normal (TAPSE 23 ± 3 mm), and in line with the NYHA class. ACTpo was reduced in the patients with a systolic PAP of < 46 mm/Hg (p > 0.001) and positively correlated with DLCO (p > 0.001) and the hemodynamic data.There was a good correlation between ACTpo and PVR (hemodynamic data) .Although they need to be confirmed by studies of larger series of patients, our findings suggest that, in comparison with hemodynamic data, non-invasive echocardiographic measurements are an excellent means of identifying early-stage PAH. Systemic sclerosis is a chronic disease essentially due to microvascular abnormalities, antibodies and a fibroblast production that leads to excessive collagen levels, and skin and viscera fibrosis-3.The most recent data show that the prevalence of systemic sclerosis from 1977 to 1980 was 12.6-25/100,000, with an incidence of 0.06-1.9/100,000. The recorded mean age of the patients at the time of onset is between 45 and 65 years, this data does not reflect the real age as the symptoms may appear many years before the first specialist assessment. The main pulmonary complications are pulmonary fibrosis and pulmonary arterial hypertension (PAH): interstitial lung disease is observed in 70% of the patients with diffused systemic sclerosis, and pulmonary hypertension in 35% of those with limited systemic sclerosis[As pulmonary hypertension in systemic sclerosis may not only be due to PAH, but also to interstitial lung disease and cardiac involvement-9, it isThe published frequencies of PAH in systemic sclerosis vary widely (from 5% to 35%), depending on the study population, and diagnostic methods (cardiac echo-Doppler or right heart catheterisation) and criteria. Echocardiography plays a central role in the non-invasive screening and management of patients with suspected PAH as it guarantees the early identification and treatment of a condition that is usually diagnosed at least two or three years after its onset-15.PAH and interstitial lung disease are the leading causes of death in systemic sclerosis and, as their early detection and treatment should improve morbidity and mortality,17. The 19 female patients, aged between 28 and 75 (51 ± 13); BMI (Kg/m2) 25 ± 5, NYHA class I^-II^ diagnosed with Systemic Sclerosis were enrolled between 2007 and 2009 in collaboration with the Rheumatic Department of the University Hospital of Parma .All patients had standard pulmonary function tests, including FVC and DLCO; auto-antibodies (ANA) including anti-centromere, anti-Scl-70 were performed as available from commercial laboratories.A chest radiograph and a high resolution CT scan (HCRT) were performed to select patients without significant pulmonary fibrosis.Patients without significant pulmonary fibrosis with reduced lung volumes, left heart dysfunction and significant valvular disease were enrolled. [see Additional file ECG: rhythm, heart rate and strain in the right ventricleThe investigated echocardiographic parameters were PAPs , ACTpo , PVR (using the equation: PVR = TRV/TVI rvot × 10+0.16), inferioRespiratory function was tested in accordance with international recommendations using a pneumotachograph and plethysmographic cabin connected to a computer for data analysis .1), and the FEV1/FVC ratio. DLCO was calculated using the single breath method, and the test was only considered valid when the inspiratory volume was the same as at least 90% of FVC. Each variable was measured at least three times. The theoretical lung volume and DLCO values were obtained using the Quanjer and Cotes regression equations[The analysed parameters were total lung capacity (TLC), volume residue (VR), forced expiratory volume in one second  and heart rate  were continuously monitored and recorded every 10 seconds from five minutes before the walk to five minutes after returning to baseline values using a portable pulsometer . To allow for the learning effect, a pause of 60 minutes was allowed between each test.The six-minute walking test (6MWT) consists of walking along a 30-metre corridor for the longest distance possible in six minutes using a standard protocol; as the test is symptom-limited, the patients are allowed to stop and resume walking when they wish. Before and after the test, the patients' vital parameters were recorded and the patients complete a visual analogue scale (VAS) quantifying the degree of dispnea. Oxygen saturation (SPOA cardiopulmonary exercise test CPET) was performed following a standardised procedure . After t2 (mL/min), carbon dioxide production  and minute ventilation  were collected , the patients were continuously monitored by means of a 12-lead electrocardiogram  and pulse oximeter , and blood pressure was measured at two-minute intervals. Resting end-tidal CO2 pressure  was recorded as the mean value measured during the 3-minute rest period, and peak VO2 as the mean value during the last 20 seconds of the test (expressed in mL/min and mL/kg/min). Ventilatory response to exercise was calculated as a linear regression function by plotting VE against VCO2 every 10 seconds of exercise (VE/VCO2 slope).During the test, breath-by-breath VOThe patients aged more than 55 years underwent femoral right heart catheterisation using a 7F catheter thermo dilution, to evaluate systolic, mean and capillary pulmonary pressure and calculate the trans-pulmonary gradient (GTP = PAPm/CO), PVR (dynes.scm-5 = GTP/CO × 80) and cardiac output (CO). PAH was defined as a PAPm of < 25 mm/Hg and Pulmonary Capillary Wedge Pressure (PCWP) of > 15 mm/Hg. Measuring the pressure of the pulmonary occlusion makes it possible to identify the pulmonary pressure site and allows the diagnosis of the pulmonary hypertension site (pre-/post-capillary).The primary objectives were to assess the associations between DLCO% at rest and PAP, and between the echocardiographic and right heart catheterisation measurements of PVR. All of the data are given as mean values ± SD unless otherwise stated. Pearson's correlation coefficient and Bland-Altman analysis were used to compare PAPs, ACTpo and TAPSE with DLCO, VO2max%, VE/VCO2, O2 pulse, NYHA class and PVR. Stepwise forward multiple regression analysis allowed the weighting of the independent effects of the potential determinants on an independent variable. The null hypothesis was rejected when p was > 0.05.ACTpo was measured by two echocardiographers blinded to the clinical data in order to assess interobserver variability.Seventeen of the 19 patients had limited cutaneous systemic sclerosis, and two an overlap syndrome including scleroderma.The patients were selected because the results of respiratory function testing at rest (FVC/DLCO) aroused a suspicion of pulmonary vasculopathy Tab . Flow, vSystolic pulmonary pressure was high (46 ± 8 mmHg), but right ventricular function was normal (TAPSE 23 ± 3), and in line with the patients' NYHA class  (p > 0.001) that corresponded with the diffusion capacity at rest (DLCO%).Mean ACTpo and PVR were respectively 117 msc and 3.31 UW.There was a significant correlation between PAPs and NYHA class , between TAPSE and NYHA class , and between DLCO and peak VO2 (p > 0.05), and a good correlation between ACTpo and NYHA class . [see Additional file Right heart catheterisation detected PAH in 15/19 patients, and one patient had veno-occlusive pulmonary hypertension; PAPm was 30.5 mmHg and PVR 3.6 UW.There was a good correlation between ACTpo and PVR   did not reveal any signs of significant coronary artery disease.Pulmonary artery hypertension is the most frequent cause of death in scleroderma patients, and its early identification is the best means of improving survival.By allowing a non-invasive evaluation of the right atrium ventricular gradient, post-systolic tricuspid annular movement (TAPSE) and the acceleration time of right outflow , echocardiography reveals the presence of pulmonary hypertension even in patients in a less advanced functional class. The data obtained by means of invasive right heart catheterisation confirmed our echocardiographic findings, which overestimated three cases with tricuspid gradient values of > 3 m/sec -26.et al. found a good correlation between invasive and non-invasive (echocardiographic) measurements of PAPs , but other authors have found discrepancies in 35% of cases[Echocardiographic measurements of the tricuspid gradient are accurate but may lead to overestimated pulmonary pressures or, less frequently, underestimates due to an incorrectly aligned regurgitated jet. Valchiery  of cases. The disAccording to the 2009 guidelines, PAH shoEchocardiography and CPET are both essential for screening patients at risk of developing PAH, which in any case needs to be confirmed by catheterisation, which also provides prognostic data that are useful for therapeutic purpose-29.The alterations in cardiorespiratory function described above represent initial signs of pulmonary and cardiac vessel impairment in patients with systemic sclerosis. Echocardiographic findings non-invasively reveal the presence of increased pulmonary pressure and pulmonary vascular resistance, morphological changes, and functional abnormalities in right ventricular parameters, which cannot be identified by means of catheterisation. The early recognition of vascular involvement together with a multidisciplinary approach to the illness should lead to better therapeutic results,31.The main limitation of this study is the small number of patients, and so the findings need to be confirmed in larger series. Misalignment due to the equalisation of pressure between the right atrium and ventricle may lead to underestimated echocardiographic calculations of PAPs and PVR, but we found a good level of inter-observer agreement concerning tricuspid regurgitation velocity and pulmonary outflow acceleration time (p > 0.5).1: Forced expiratory volume in 1 second; FVC: Forced vital capacity; GTP: Transpulmonary gradient (PAPm/CO); MVV: Maximum Voluntary Ventilation; NYHA: New York Heart Association; O2Pulse: Oxygen Pulse (VO2/HR); PAH: Pulmonary Arterial Hypertension; PAPm: Pulmonary Artery Pressure mean; PCWP: Pulmonary Capillary Wedge Pressure; PVR: Pulmonary Vessel Resistance; RV: Residual Volume; SS: Systemic Sclerosis; TAPSE: Tricuspid annular plane systolic excursion; TLC: Total Lung Capacity; VAS: -Visual analogic Scale; VO2: Oxygen Consumption; VCO2: Carbon Dioxide production; VE/VCO2 slope: CO2 Ventilatory equivalent slope; VE/VO2 slope: O2 Ventilatory equivalent slope; 6MWT: 6 Minute Walking Test.ACTPO: Pulmonary outflow acceleration time; BR: Breath reserve (MVV-VEmax); CO: Cardiac Output; CPET: Cardio Pulmonary Exercise Test; DLCO: Carbon monoxide lung diffusion.; FEVThe authors declare that they have no competing interests.WS conceived and carried out the study and drafted the manuscript. AC participated in the design of the study and performed the statistical analysis. DS, FM and PPDA contributed sending some scleroderma patients, essential for the study. MAC performed right heart catheterisation. DO, DA and TG participated in its design and coordination.All authors read and approved the final manuscript.All patients provided written informed consent to participate in the researchPatient's data. Seventeen of the 19 patients had limited cutaneous systemic sclerosis, and two an overlap syndrome including scleroderma.Click here for fileECHO an RHC data. There was a significant correlation between TAPSE and NYHA class  and a good correlation between ACTpo and NYHA class . Right heart catheterisation detected PAH in 15/19 patients: PAPm was 30.5 mmHg and PVR 3.6 UW.Click here for file


Background. Microemboli are a widely recognized etiological factor of cerebral complications in cardiac surgery patients. The present study was aimed to determine if size of left cardiac chambers relates to cerebral microembolic load in open heart operations. Methods. Thirty patients participated in the study. Echocardiography was performed in 2-3 days before surgery. A transcranial Doppler system was used for registering intraoperative microemboli. Results. Preoperative left atrium and left ventricular end-systolic and end-diastolic sizes significantly correlated with intraoperative microembolic load . The associations between left ventricular diameters and number of cerebral microemboli remained significant when cardiopulmonary bypass time was included as a covariate into the analysis. Conclusions. The present results demonstrate that increased size of left heart chambers is an influential risk factor for elevated cerebral microembolic load during open heart operations. Mini-invasive surgery and carbon dioxide insufflation into wound cavity may be considered as neuroprotective approaches in patients with high risk of cerebral microembolism. Microemboli are a widely recognized etiological factor of cerebral complications in cardiac surgery patients. Our group found significant associations between microembolic load and deliria and cognitive dysfunction after on-pump operations , 2. MicrProgress in on-pump technologies resulted in reduced cerebral microembolic load and, therefore, neurological complications during contemporary cardiac operations. Membrane oxygenators instead of bubble ones and arterial line filters are used at present in the majority of cardiac surgery centers. Off-pump surgery, epiaortic scanning, minimized aortic manipulations, and perfusionist interventions were introduced as emboli lowing approaches. Hence, correct knowledge about potential sources of microemboli increases quality of surgery and, therefore, improves outcomes. However, it is still unclear why the variability of cerebral microembolic load is so extensive in patients, which are operated on by the same surgical team using the same cardiopulmonary bypass circuit and surgical technologies. The large variability of intraoperative microembolic load in spite of the similar surgical methodology implicates unknown patient characteristics as possible contributing factors to the quantity of intraoperative microembolism.The majority of microemboli occurring during cardiac surgery are air bubbles . Air entAir tends to accumulate in the highest parts of the heart including left ventricular apex, left atrial appendix, and the upper wall of the left atrium . Air bubThe present study protocols were reviewed and approved by the academic council of Bakulev's cardiovascular surgery center. The study design was explained to patients, and each patient gave an informed consent to participate. Inclusion criteria were, age 16–69 years old, preoperative cardiac ejection fraction >40%; and availability of middle cerebral arteries (MCAs) to be insonated through the transtemporal windows. Exclusion criteria were: emergency and reoperative surgical procedures, previous cerebrovascular accident, and serious concomitant non-cardiac disease. A total of 30 patients were included into the study. The patients underwent operations on aortic and/or mitral valve, with or without concurrent CABG. The preoperative and intraoperative characteristics of patients are presented in μm arterial filter. Nonpulsatile pump flow rates were maintained between 2.4 and 2.6 L ∗ min−1  ∗ m−2, and mean perfusion pressure at 60 mm Hg. The operations were accomplished during moderate hypothermia (28°C). All patients underwent median sternotomy, the aorta was cross-clamped, and the heart was arrested with anterograde cold pharmacological cardioplegia by solution of custodioli. Topical ice saline was used as an adjuvant to myocardial protection.The protocols of anesthesia and surgical techniques were standardized. Diazepam and morphine served as premedication. Anesthesia was induced and maintained with propofol, fentanyl, and pancuronium. The perfusion apparatus consisted of the Stökert S3 roller pump (Germany), DIDECO-703 membrane oxygenator , and a 40 Echocardiography was performed with a Hewlett Packard Sonos 5500 ultrasound system with a 4 MHz transducer. Each patient underwent echocardiographic assessment in 2-3 days before surgery. Subjects were studied with M-mode and two-dimensional echocardiography. Left atrium diameter was measured in the parasternal long axis view from trailing edge of the posterior aortic root—anterior left atrium complex to the posterior left atrium wall. Left ventricular end diastolic and systolic dimensions were determined from standard M mode measurements. Absolute values of cardiac dimensions were not normalized.A 2-MHz Transcranial Doppler (TCD) system  was used for continuous bilateral monitoring of middle cerebral artery blood flow  during the operation. The probes were fixed transtemporally by a head brace. Registration of microembolic signals was conducted from the initiation to complete discontinuation of CPB. MEs were defined as transient, short-duration (<300 ms), high-amplitude signals with intensity of >5 dB higher than background noise and which were accompanied by a characteristic high-frequency “click”. Settings for ME detection were highpass filter—120 Hz, lowpass filter—1100 Hz, dynamic range—96 dB, temporal overlap—60%, and sample volume—10 mm. The stored raw data were revised rigorously after the surgery to verify the number of intraoperative ME. The summarized value of microembolic load was included into the analysis.P <  .05. The linear regression analyses were performed in order to evaluate the combined effects of several variables of interest on the variance of microembolic load. Predictor variables were entered into a simultaneous regression model.Statistical analysis was performed using SPSS software for windows . The data were tested for normality with the Kolmogorov-Smirnov test and found to be normally distributed. Correlation analyses were conducted using bivariate and partial Pearson's tests. The correlations were considered significant at a probability level of rs = 0.48, 0.57 and 0.53, ps < .01, resp.) , whereas correlation between left atrium diameter and microemboli did not reach significance . When any of left ventricular sizes was included into the regression model along with CPB time, both variables explained 42% of variance of cerebral microembolic load during open heart operations.Preoperative left atrium diameter and left ventricular end-systolic and end-diastolic sizes significantly correlated with intraoperative microembolic load in open heart operations  . As CPB The present results demonstrate that increased size of left heart chambers is an influential preoperative risk factor for elevated cerebral microembolic load during open heart operations. Although patients with enlarged hearts underwent longer CPB, the effects of cardiac size on cerebral microemboli were independent from CPB time. It is important to note that we studied the total number of intraoperative microemboli which entered the cerebral circulation during the whole CPB period. Nevertheless, cardiac size explained the considerable proportion of variance of intraoperative microembolic load in our patient cohort. Our findings implicate discussion of two important aspects: if gaseous microembolism is neurologically significant and contemporary approaches to prevention of air microembolism in open heart surgery.Martens and colleagues [2 induced multiple ischemic lesions in both homolateral and heterolateral brain hemispheres in experimental animals. Air bubbles occluded vessels and induced multiple small nonperfused areas in porcine retina in the study of Herren and colleagues [We used Transcranial Doppler system for registration of cerebral microemboli. The sensitivity of Doppler technology to gaseous microbubbles is much higher in comparison with particulate emboli ; therefolleagues  bolus inlleagues .In our relatively young patient cohort we found linear associations between intracerebral microembolic load to left hemisphere and postoperative verbal memory decline, and between microemboli to right hemisphere and nonverbal memory decline . In the Overall, the cited experimental and clinical studies evidence that intraoperative gaseous embolism is an important neuropathogenic factor. Although air microembolism is a routine event during cardiac and noncardiac operations , it shouIntraoperative cerebral microembolism occurs not only during on-pump procedures; however, any surgical manipulation and even peripheral vein puncture induce air entrapment into systemic and cerebral circulation . Therefo2 insufflation group in comparison with control patients. The same research group found significantly more pronounced ischemic brain damage in pigs after intracarotid air injection in comparison with animals after intracarotid carbon dioxid injection [Deairing technologies are actively investigated at present as well , 17, 18.njection .Cardiopulmonary bypass with a prime of perfluorocarbon emulsions was shown to reduce air embolism in experimental studies , 19. HowIn conclusion, patients with enlarged left cardiac chambers are at high risk of cerebral air embolism during open heart surgery. Prevention of air embolism is of importance as intraoperative microembolic load linearly correlates with brain damage. Mini-invasive surgery and carbon dioxide insufflation into wound cavity may be introduced as neuroprotective technologies in cardiac operations. Other embolism lowing methods need further research.


Inosine, a break-down product of adenosine has been recently shown to exert inodilatory and anti-inflammatory properties. Furthermore inosine might be a key substrate of pharmacological post-conditioning. In the present pre-clinical study, we investigated the effects of inosine on cardiac function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation.Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle , or inosine . Left ventricular end-systolic pressure volume relationship (ESPVR) was measured by a combined pressure-volume-conductance catheter at baseline and after 60 minutes of reperfusion. Left anterior descendent coronary blood flow (CBF), endothelium-dependent vasodilatation to acetylcholine (ACh) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined.The administration of inosine led to a significantly better recovery (given as percent of baseline) of ESPVR 90 ± 9% vs. 46 ± 6%, p < 0.05. CBF and was also significantly higher in the inosine group . While the vasodilatatory response to SNP was similar in both groups, ACh resulted in a significantly higher increase in CBF  in the inosine group.Application of inosine improves myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest. Ischemia-reperfusion injury is a well-known phenomenon after cardiac surgery. Independent of the technique of cardioplegia, temporary dysfunction of biventricular contractility can frequently be observed. Even if cardiac dysfunction is not clinically evident, a reduction of myocardial contractility may occur as described in a study in humans using pressure-volume relationships . In addiExtra-corporal circulation is also known to induce a systemic inflammatory reaction with free radical release leading to secondary organ injury. During ischemia, cellular ATP is degraded into AMP, adenosine, inosine and hypoxanthine. Adenosine and its primary metabolite inosine are ubiquitous nucleosides that can be released from ischemic or reperfused tissue . AdenosiAs the use of inosine for prevention of reperfusion injury in the context of cardiopulmonary bypass has not yet been investigated, the aim of the present study was to test the hypothesis that treatment with inosine during reperfusion improves myocardial, and endothelial function in a clinically relevant canine model of extracorporal circulation.12 dogs (foxhounds) weighing 21 to 35 kg (24.4 ± 1.5 kg) were used in these experiments. All animals received human care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health . The experiments were approved by the Ethical Committee of the Land Baden-Württemberg for Animal Experimentation.2 (FiO2 = 60%) at a frequency of 12-15/min and a tidal volume starting at 15 ml/kg per minute. The settings were adjusted by maintaining arterial partial carbondioxide pressure levels between 35-40 mmHg. The femoral artery and vein were cannulated for recording mean arterial pressure (MAP) and taking blood samples for the analysis of blood gases, electrolytes and pH, and parameters of blood coagulation. Basic intravenous volume substitution was carried out with Ringer's solution at a rate of 1 ml/min/kg. If necessary, the rate of volume substitution was modified according to the continuously controlled input-output balance in order to maintain cardiac output at baseline levels. According to the values of potassium, bicarbonate and base excess, substitution included administration of potassium chloride and sodium bicarbonate (8.4%). Neither catecholamines nor other hormonal or pressor substances were administered. Rectal temperature and standard peripheral electrocardiogram were monitored continuously.The dogs were premedicated with propionylpromazine and anesthetized with a bolus of pentobarbital , paralyzed with pancuronium bromide (0.1 mg/kg as a bolus and then 0.2 mg/kg/h i.v.) and endotracheally intubated. The dogs were ventilated with a mixture of room air and OAfter left anterolateral thoracotomy in the fourth intercostal space, pericardiotomy and isolation of the great vessels a perivascular ultrasonic flow probe was attached to the ascendent aorta. Aortic pressure was monitored with 5F Millar catheter tip manometer .After systemic anticoagulation with sodium heparin (300 U/kg) the left subclavian artery was cannulated for arterial perfusion. The venous cannula was placed in the right atrium. The extracorporeal circuit consisted of a heat exchanger, a venous reservoir, a roller pump and a membrane oxygenator primed with Ringer lactate solution (1000 ml) supplemented with heparin (150 U/kg) and 20 mL sodium bicarbonate . Hypothermic CPB was performed for 90 minutes at a lowest temperature of 28 °C. After initiation of CPB, the hearts were arrested with 1000 ml crystalloid cardioplegia (Custodiol). Twenty minutes before cross-clamp removal, rewarming was initiated. After 60 minutes the aortic crossclamp was released and the reperfusion phase was initiated. All animals were weaned from CPB without inotropic support. After weaning from CPB, heparin was antagonized by protamine iv over 10 minutes and the animals were monitored for one hour. Thereafter, the hearts were excised for further investigation.Twenty minutes before cross-clamp removal, rewarming was initiated. After 60 min of cardiac arrest, the aorta was declamped, and the heart was reperfused with normothermic blood in the bypass circuit. If necessary, ventricular fibrillation was counteracted with DC cardioversion of 40 J. Ventilation was restarted with 100% oxygen. All animals were weaned from CPB without inotropic support 20 min after the release of the aortic cross clamp. Each animal underwent 90 min of CPB with 60 min of cardiac arrest.Two groups of animals were studied. Group 1 (n = 6) received placebo, group 2 (n = 6) received 100 mg/kg inosine during reperfusion. The applied dose of inosine is based on previous dose-response and pharmacokinetic studies.Left and right ventricular systolic pressure , maximum and minimum pressure development , end-diastolic pressure  and cardiac output (CO) as the equivalent of aortic flow were monitored continuously. Stroke volume (SV) was calculated from the integrated flow signal and was used to calibrate the volume signal from the conductance catheter. Parallel conductance was estimated by rapid injection of one ml of hypertonic saline into the pulmonary artery or vena cava superior, respectively.The volume signal provided by the conductance catheter was registered continuously  and computed by the Conduct PC software . Left and right ventricular pressure-volume loops were constructed on-line. Vena cava occlusions were performed to obtain a series of loops for calculation of the slope (Ees) and intercept (V0) of the left and right ventricular end-systolic pressure-volume relationships. In addition, the slope of the left ventricular end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW) were calculated as load-independent indices of myocardial contractility.-7 mol) and endothelium-independent vasodilatation after administration of sodium-nitroprusside . The vasoresponse was expressed as percent change of baseline coronary blood flow.Coronary blood flow (CBF) was measured by an ultrasonic flow meter placed on the left anterior descendent coronary artery. Coronary endothelium-dependent vasodilatation was assessed after intracoronary administration of a single bolus of acetylcholine . Paired t-test was used to compare two means within groups. Individual means between the groups were compared by one-way analysis of variance followed by an unpaired t-test with Bonferroni correction for multiple comparisons and the post-hoc Scheffe's test. A probability value less than 0.05 was considered statistically significant. In the figures only the significances between the groups were indicated. Significant changes over the time within each group were indicated in the text.p < 0.05) in the control group while it remained unchanged in the inosine group. CO did not differ significantly between the groups. However, it should also be noted that CO showed a clear decreasing tendency within the control group without reaching the level of significance [Table Hemodynamic variables are shown in Table ce Table .Left ventricular function was identical in both groups at baseline Figure . Myocardp < 0.05) in the control group, but it increased in the inosine group [Figure Coronary blood flow was similar in both groups before cardioplegic arrest. After 60 min of reperfusion, coronary blood flow decreased significantly (p Figure . Endothep Figure  but remaIn this study, the benefits of the application of inosine during reperfusion were assessed after cardiac arrest in a canine model of extracorporal circulation. We have shown that inosine improves left ventricle and endothelial function recovery after cardioplegic arrest.Until recently, inosine was considered an inactive purine metabolite in most biological systems, but several recent studies have shown that it has immuno-modulatory , neuroprThe most cardiac surgical procedures require cardiopulmonary bypass and cardioplegia, which causes ischemia-reperfusion injury. Ischemia-reperfusion injury initiates pathophysiological cascades including an inflammatory response with liberation of cytokines and free radicals. Triggered by peroxynitrite-induced DNA single-brand breaks, PARP catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis, and the reduction of intracellular high-energy phosphates in the reperfused heart. In various types of ischemia-reperfusion, the prevention of PARP activation results in better preservation of the high-energy phosphates, resulting in an improved energy status -19. It i+, thereby maintaining some vital cellular functions. Inosine may exert some of its cytoprotective effects under ischemia by providing an emergency energy source, when glucose is insufficient to support cellular functions. The above hypothesis is supported both by several reports that cellular ATP levels were elevated in ischaemic or hypoxic cells treated with adenosine or inosine [The increase of coronary blood flow during reperfusion contributes also to the improvement of cardiac function. Previous studies demonstrated that inosine increased coronary flow dose-dependently and, as a consequence, the function of the reperfused heart ,22. Our  inosine -30 As inIn summary the results of this study showed that treatment with inosine during the reperfusion markedly improved post-ischemic myocardial and endothelial function after cardioplegic arrest in the setting of a cardiopulmonary bypass. Based on the promising data of the present study, inosine is supposed to utilize in the clinical usage. However, further clinical investigations are needed.The authors declare that they have no competing interests.All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; have been involved in drafting the manuscript or revisiting it critically for important intellectual content and have given final approval of the version to be published.


Because of an extensive septal necrosis, the manifestation of the initial ventricular activation forces decreases in the precordial leads. With left bifascicular block (LASB + LPSB), the first ventricular activation forces become more evident and the electrical signs of septal necrosis can be concealed. In the presence of a trifascicular block, manifestation of the first ventricular electromotive forces diminishes again and the electrical signs of septal necrosis become evident once more. Small Q waves are present in leads V2 to V6. An associated left bifascicular block reduces the electrical manifestation of dead tissue: QS complexes persist only in V3 and V4. In turn, a coexisting trifascicular block causes the presence of QS complexes from V2 to V5. Extensive anterior necrosis + peripheral blocks. This necrosis is manifested by QS complexes from V5 and V6. Consequently, the electrical signs of necrosis are reduced or abolished. Due to a trifascicular block, wide and slurred QS complexes are recorded in aVF, II, III and sometimes in V5 and V6.Posteroinferior necrosis + peripheral blocks. Electromotive forces of the ventricular activation shift upward, due to a posteroinferior necrosis and QS or QR complexes are recorded in leads aVF, II and III. An associated left bifascicular block displaces the main electromotive forces downward, posteriorly and to the left, due to a delay of the posteroinferior activation fronts. The ventricular complexes become positive and wider in all leads, reflecting the potential variations of the inferior portions of the left ventricle: aVF, II, III, sometimes V Fascicular or peripheral blocks can be diagnosed, based on two types of data: morphologically by the slurred vertex of the R wave only in leads exploring the affected regions and chronologically by the prolonged time of onset of the intrinsicoid deflection (TOID) in these leads. It seems correct to define as bifascicular block the one concerning two subdivisions of the same bundle, right or left, and as bilateral block that involves the right and left conduction systems.It is justified to diagnose ventricular peripheral blocks in clinical tracings on the basis of experimental findings. For this, we produced a left anterior subdivision block (LASB) -4, as we1). The resultant vector of this depolarization process is manifested directly only in aVL Fig. (2).LASB delays and modifies the ventricular depolarization process in the superior regions of the left ventricle. Consequently, the left basal vector III points upward and to the left. In fact, the ventricular activation process progresses from the middle left septal mass toward the upper left septal mass and the basal parietal wall Fig.  reproduces intra-cavitary tracings showing the delayed activated myocardium in the right ventricle (V) near the outflow tract (ablation catheter).In turn, the right anterior subdivision block (RASB) affects the superoanterior region of the ipsilateral ventricle. The late depolarization of this ventricle occurs in the upper right septal mass and parietal wall, as well as in the ventricular outflow tract. Hence, the right III vector, directed upward and to the right, accounts for the S4).LPSB produces a delay of the activation process in the left posteroinferior septal mass and left diaphragmatic parietal wall. For this, the main resultant vector of the left ventricular depolarization (III left vector) is oriented downward and to the left. This vector is the last of the ventricular activation process and is seen in the lower left leads, i.e., aVF Fig. , ME (unipolar in epigastrium), and aVF in horizontal hearts.RPSB delays the activation of the posteroinferior right septal mass and of the adjacent right ventricular wall. It is manifested in leads V6: TOID is prolonged in these leads. The segmental activation delays in the free left ventricular wall can be represented by a mean resultant vector.In the presence of an uncomplicated left bifascicular block, the ventricular activation process advances forward ,12. Cons5), three main resultant vectors of normal ventricular depolarization in the human heart, are drawn. On the right, the main resultant vectors of ventricular activation, in the presence of left bifascicular block [On the left side of Fig.  persist.When the septal inactive myocardium is associated with a left bifascicular block (LBFB), the activation process is delayed in the posterior and the anterosuperior portions of the interventricular septum . Therefo2 and qR morphologies, with slurred R waves, in V5 and V6, whereas QS morphologies persist in V3 and V4 [LBFB causes the inscription of small positive initial deflections in V3 and V4 . Hence t3 and V4 -4 and co6. In this case, the ECG is similar to that of a LBBB of intermediate degree [5 and/or V6. Summarizing, the ventricular complexes become positive, wide, in the low leads and in the left precordial leads. Because of this, the electrocardiographic signs of necrosis are reduced or can disappear. The electrical curves could suggest the presence of an aberrant LBBB of intermediate degree, but the left intraventricular QS complexes allow us to discard this possibility.Because of this association, the delay in the activation of the free left ventricular wall due to both left peripheral blocks, can balance again the electromotive forces of the ventricular depolarization . Neverthe degree . The fir6), recorded in a 63-year-old man, is suggestive of left bifascicular block: R waves appear slurred in aVL and aVF, but the TOID is more prolonged in aVF (100 msec) than in aVL (55 msec). Moreover, the manifestation of the first septal vector persists in V1 and V6, while the morphology of the left intraventricular complexes (LVM) is normal: QS. In turn, the small slurred Q waves in aVF, lasting 40 msec, suggest the presence of inactive myocardium in the diaphragmatic left ventricular wall.The ECG of Fig. . This block is really a bilateral block, but is called “Trifascicular” following common usage (1 and V2 resemble those of an intermediate degree right bundle branch block (RBBB) [H). A prominent clockwise RH loop exists, with a delayed vertex crossing the Z axis anteriorly to the E point and at around 0.07 sec.Under experimental conditions, it is possible to produce a trifascicular block, i.e., left bifascicular block + right bundle branch block, without an atrioventricular block. In fact, the excitation wave can arrive at the middle left septal mass through intermediate subdivisions, arising from the left main bundle. The delayed activation process in both ventricles reduces their asynchronism. For this reason, the unipolar morphologies in leads Vk (RBBB) . Otherwik (RBBB) , and by 6, as well as R’ in V1 and, occasionally, late “r” waves in aVR. The direction of the fourth vector accounts also for the small S loop of the vectorcardiographic ventricular curves.Manifestation of the first vector is delayed. It is oriented more to the right than in the presence of isolated RBBB. The left second vector is displaced forward. The fourth vector of RBBB still points forward and slightly to the right, which explains the presence of small S waves in VThe main forces of the repolarization process are directed downward and backward. Nevertheless, T waves may change according to the underlying heart pathology.7) shows an outline of the main resultant vectors of the ventricular depolarization process in the presence of a trifascicular block. When a RBBB is associated with a LBFB, the first vector is slightly delayed and directed more to the right, the second vector shifts forward, the third vector of RBBB is counterbalanced by the main vector of the left bifascicular block. Therefore, the 0.06-sec vector of ventricular activation points to the left and forward and the fourth vector remains practically unchanged.Fig.  or enlargement of the right atrium could exist, responsible for the inscription of Q waves. In any case, high precordial unipolar recordings must be obtained in the third and fourth left intercostal spaces in order to discard the presence of pathological Q waves.When a trifascicular block coexists with septal inactive myocardium, the initial forces of ventricular depolarization, oriented forward and to the right, are reduced . This chr septum . In thes3R, just as can be seen in the presence of RBBB complicating a septal necrosis [Electrocardiographic signs of septal necrosis become more evident in the presence of a trifascicular block than with a left bifascicular block. The behavior of intermediate forces of ventricular depolarization allows detecting the trifascicular block. These forces are oriented forward, as in the case of RBBB, and to the left, as in the case of LBBB. The changes in the fourth vector depend on the extent of septal inactive myocardium. This vector is now located in a middle position or distorted to the left, explaining the smaller voltage of the late R wave in the right precordial leads and Vnecrosis . The sig2 until V5 and qRS in V6, sometimes qR from V1 until V6. QS complexes in V5 and V6 could be due to local electrical effects picked up only in the near unipolar leads [If the septal inactive myocardium is very extensive, the mean vector of ventricular depolarization is directed now upward and forward, but it is always oriented to the left. Consequently, negative or predominantly negative ventricular complexes are registered in precordial leads: QS from Var leads . The comar leads . The resIn these conditions, the ventricular depolarization can be synthesized in the following points :The first septal vector, of increased voltage, is oriented upward, forward, and to the right. This vector is responsible for the initial negativity of ventricular complexes in the standard leads and aVF.o in both frontal and horizontal planes). The delayed second vector, originated in the free left ventricular wall, is directed upward, backward, and to the left . Sometimes, these complexes are recorded in V5 and V6 too, mimicking a lateral inactive myocardium. Delay and slowness of the ventricular depolarization, due to these associated blocks, are manifested through slurred R waves and unequally prolonged TOID in leads exploring damaged myocardial regions. The orientation of the main resulting vectors of ventricular depolarization, in the presence of a trifascicular block, is shown in Fig. (7).Therefore, the ventricular complexes are slurred, and wide QS are present in L8) was recorded in a 36-year-old man with cardiomyopathy. The inferior tracing shows a trifascicular block. Sinus rhythm persists with a slight increase of P-R from 0.16 sec to 0.18 sec and a QRS-duration of 0.15 sec. ÂQRSF is at -20o. Slurred qR complexes are registered in leads I and aVL, where the onset of the intrinsicoid deflection is around 0.08 sec, rS morphologies are inscribed in leads III and aVF. The TOID is around 0.04 sec in leads III and aVF. RBBB is recognizable in lead V1. The unipolar morphologies are rs in aVR, qR in V5 and V6 with TOID= 0.06 sec. The diagnosis of trifascicular block is supported also by the orientation of ÂQRSF, the slurred R waves in leads aVF and V6, and the absence of a terminal R wave in aVR, which must be prominent in the presence of LASB associated with RBBB. SÂT is oriented downward, backward and slightly to the right, whereas in the previous ECG it was directed upward, forward, and to the left. The slurred Q waves, of 0.04 sec, in V4 and V5 suggest the presence of inactive septal myocardium.The ECG of Fig. (The early diagnosis of a trifascicular block seems to be particularly useful due to an impending severe A-V conduction disturbance.It is very useful to establish the diagnosis of peripheral blocks, in clinical electrocardiograms, on the bases of experimental findings. Some years ago, we published the electrocardiographic manifestations of dead myocardium associated with peripheral monofascicular blocks, emphasizing that left ones, LASB and LPSB, can conceal the electrocardiographic signs of the inactive anteroseptal and posteroinferior myocardium, respectively .via intermediate strands of the left bundle. Consequently, a left bifascicular block, resembling an intermediate degree LBBB [6, often by the manifestation of the first septal vector also. The vectorcardiographic ventricular curves are diphasic and show initial and terminal slurs. A left bifascicular block associated with an extensive anterior necrosis reduces the electrical manifestation of dead myocardium: QS complexes persist only in V3 and V4. This block, complicating a posteroinferior necrosis, causes the ventricular complexes to become positive and wider in all leads [5 and V6. Therefore, the electrical signs of necrosis are reduced or concealed.We produced also left bifascicular and trifascicular blocks in canine hearts  and publree LBBB , can be ll leads . This fa2 to V5. Wide and slurred QS complexes are recorded in aVF, II, III, and sometimes also in V5 and V6 when the mentioned conduction disturbance is associated with a posteroinferior necrosis.A trifascicular block delays the activation sequence in both ventricles. Therefore, the asynchronism between the electromotive forces of the ventricles is lessened . This co