Common conditions such as obesity and hypertension result in hemodynamic alterations that will induce remodeling of the left ventricle (LV). However, differences between the genders in the relationship of hemodynamics to LV geometry are not well known.The present study aims to investigate differences between the genders in this respect, in a sample of elderly persons.Echocardiography and Doppler was performed in a population-based sample aged 70 - The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 922).Hemodynamic patterns obtained by echocardiography and Doppler were evaluated in relation to four LV geometric groups .No significant difference between the genders was observed regarding the prevalence of the LV geometric groups.Mean values of most evaluated echocardiography and Doppler variables differed between men and women, such as LA, IVS, LVEDD and IVRT, but the relationship of hemodynamic variables to LV geometric groups did not differ between the genders.Although mean values of many echocardiographic variables differed between men and women, the LV geometric adaptations to a given hemodynamic load appear similar in both genders. Alteration of the left ventricle (LV) as a consequence of hypertension is a well known phenomenon and numerous studies have demonstrated that LV hypertrophy is a strong and independent predictor of cardiovascular events -4.Several studies have demonstrated the impact of hypertension both as isolated systolic hypertension and in combination with diastolic hypertension on LV structures -9.Different patterns of LV geometry as a result of hypertension were first described in a study by Ganau and co-workers in 1992 . That stSurprisingly, the study demonstrated that the most common LV hypertrophy (LVH) category was not the classical one, concentric hypertrophy. 52% of the hypertensive patients had a completely normal LV mass and RWT. 13% had a normal LV mass, but increased RWT and were classified as concentric remodeling. Of the remaining persons 27% had an eccentric LV hypertrophy and only 8% had concentric LVH. Furthermore, it was shown that different types of LV geometrical adaptations were associated with different hemodynamic patterns. A 10-year follow-up of 253 persons with initially uncomplicated essential hypertension revealed that persons with concentric LV geometry had the highest risk for cardiovascular death (31%) and morbid events (11%). The lowest risk was observed in the group with normal LV geometry (no cardiovascular event and 11% risk for morbid events) [Andrén and co-workers investigated a population-based sample of 584 elderly men . AlteratIn addition to different hemodynamic patterns the geometric groups often have different clinical backgrounds. Persons with coronary heart disease and cardiomyopathy tend to have a higher prevalence of eccentric LVH. Concentric LVH is observed more often in persons with hypertension or valvular disease (aortic stenosis) and patients with diabetes or metabolic syndrome tend to have a higher prevalence of concentric remodeling ,13A study by Krumholz and co-workers demonstrated the association of isolated hypertension with increased left ventricular mass in men and women, the geometric pattern of increased LV mass differed by sex. Women demonstrated mainly a pattern of concentric hypertrophy while an eccentric pattern mainly was observed in men .Thus, few studies have reported gender differences in proportions of LV geometric patterns in the general population. Our primary aim in the present study was therefore to study gender differences in the prevalence of LV geometric groups. A secondary aim was to investigate differences between genders regarding hemodynamic patterns in different LV geometric groups.th birthday. 1016 subjects participated giving a participation rate of 50.1%. The study was approved by the Ethics Committee of the University of Uppsala. Signed informed consent was given by all subjects.Eligible were all subjects aged 70 living in the community of Uppsala, Sweden. The subjects were randomly chosen from the register of community living and invited shortly following their 70Approximately 10% of the cohort reported a history of coronary heart disease, 4% reported stroke and 9% diabetes mellitus. Almost half the cohort reported any cardiovascular medication (45%), with antihypertensive medication being the most prevalent (32%). Fifteen percent reported use of statins, while insulin and oral antiglycemic drugs were reported in 2 and 6%, respectively.In the sample, 22% were on beta-blocking drugs, 11% on calcium antagonists, 12% were on diuretics, 8% were taking ACE-inhibitors and 8% were on regular medication with an ARB.Prior to their examination, subjects completed a questionnaire concerning their medical history, regular medication and smoking habits.All subjects were investigated in the morning after an overnight fast and no medication was taken on the day of the investigation. Participants were in the supine position in a quiet room at constant temperature.Recordings of height, weight and abdominal and hip dimensions were performed and blood samples were taken and analysed by standard laboratory techniques.A comprehensive two-dimensional and Doppler echocardiography was performed with an Acuson XP124 cardiac ultrasound unit  A 2.5 MHz transducer was used for the majority of the examinations. Presence of stenosis or regurgitation in the mitral and aortic valves was recorded by use of colour and continuous Doppler. A complete echocardiographic examination was only successfully performed in 922 due to technical problems to obtain images of good quality in 94 subjects.LV dimensions were measured with M-mode on-line from the parasternal projections, using a leading edge to leading edge convention. Measurements included left atrial diameter (LA), interventricular septal thickness (IVS), posterior wall thickness (PW), left ventricular diameter in end diastole and end systole . Left ventricular relative wall thickness (RWT) was calculated as (IVS+PW)/LVEDD. Echocardiograms were read on-line. M-mode recordings were used for calculations of LV dimensions, such as LVEDD, LVESD, IVS and PW, being the basis for calculations of LV mass.2.7 to obtain left ventricular mass index (LVMI).Left ventricular mass (LVM) was determined from the Penn conversion. LVM was then indexed for heightLV geometry was also divided into 4 categories according to Ganau et al. A normal LV geometry was considered to be present if LVMI was normal (< = 51 g/m2.7) and relative wall thickness (RWT) < 0.45 Concentric LVH was defined as LVMI above the threshold for LVH together with RWT > = 0.45, but if RWT was below this cut-off for RWT eccentric LVH was present. If LVMI was normal but RWT > = 0.45 the LV geometry was denoted as concentric remodeling.Left ventricular volumes were calculated according to the Teichholz formula 7*D3/(2.4+D) and from that value ejection fraction (EF) was calculated.The left ventricular diastolic filling pattern of the mitral inflow was obtained from the apical transducer position with the pulsed Doppler sample volume between the tips of the mitral leaflets during diastole. The peak velocity of the early rapid filling wave (E wave) and the peak velocity of atrial filling (A wave) were recorded and the E to A ratio (E/A) was calculated. Left ventricular isovolumetric relaxation time (IVRT) was measured as the time between aortic valve closure and the start of mitral flow using the Doppler signal from the area between the left ventricular outflow tract and mitral flow. Presence of a restrictive filling pattern was evaluated in subjects with a reduced EF. This pattern was considered to be present if E/A-ratio was >1.5 and IVRT < 96.Also the time between the A and the next E-wave was measured (A-E) together with the ejection time . The myocardial performance index  was calculated as: A-E minus ET divided by ET. MPI was not included in the original protocol and was therefore only measured in the last 852 consecutive subjects.Subjects with significant valvular disease were excluded from the analysis (n = 5).StatView  was used for statistical analysis. If variables failed to show normal distribution (the E/A-ratio) a natural logarithmic transformation was done. Analysis of Variance (ANOVA) was used to compare different groups and Analysis of Covariance (ANCOVA) was used for correction for gender and history of myocardial infarction. Any post-hoc analysis was carried out with Bonferroni correction. Chi-square analysis was used to relate two nominal variables. Only p-values < 0.05 were accepted as statistically significant.There were no significant differences regarding the frequency of antihypertensive treatments between the genders. Systolic blood pressure and heart rate differed significantly between the genders but there was no significant difference regarding diastolic pressure.The echocardiographic measurements indicating different geometries such as IVS, PW, LVEDD and LVESD were significantly larger in men (p < 0.0001) but on the other hand no significant difference could be demonstrated regarding RWT, LVMI, CI or TPRI between men and women.Among variables evaluating LV diastolic function, there was no significant difference in E/A-ratio (p < 0.58) between the genders but IVRT and ET were significantly shorter in men p < 0.0001)  Figure .Since there were no significant interactions between gender and the LV geometric groups  were significantly different in the pathological groups compared with the group with normal LV geometry (p < 0.0001).LV diastolic function indicators such as E/A-ratio and IVRT were significantly pathological in the abnormal LV geometrical groups (p < 0.0001) with exception for E/A-ratio in the concentric remodeling group compared with normal LV geometry. Even ET was not significantly different between the groups (p = 0.15) table .There was a highly significant difference between the groups concerning systolic hemodynamic values  (p < 0.0001). EF was lowest in the eccentric LVH group. There was no significant difference regarding MPI in the concentric remodeling group in comparison with normal LV geometry table .In order to evaluate any particular interaction between hemodynamics and gender regarding LVMI and RWT, we performed two different regression models. In the first, LVMI was the dependent variable and the hemodynamic variables CI, SBP, DBP and TPRI were independent variables together with gender. In this model CI, SBP and gender were significant independent predictors of LVMI . In a second step the interaction terms between gender and CI, as well as between gender and SBP, were investigated, but none of them were significant in the model .In the next regression model, LVMI was substituted with RWT as the dependent variable. In this case, SBP and TPRI were the significant independent predictors of RWT (p < 0.0001 for both). However, neither in this case the interaction terms between gender and SBP or between gender and TPRI were significant . Thus, taken together, the influence of the hemodynamic factors; CI, SBP, DBP and TPRI on LVMI or RWT were not found to be significantly different between men and women.In a secondary analysis of the data excluding the 129 subjects with a history of ischemic heart disease, still no significant difference was seen between men and women regarding the LV geometric pattern (p = 0.66). For the results presented in table In clinical practice there is a tendency to consider women`s hearts different from men`s hearts regarding cardiovascular risk and diseases. It is therefore relevant to study whether there are any significant differences between the genders regarding the adaptation of the LV to the different hemodynamic patterns.The relation between left ventricle geometry and hemodynamic conditions has previously been studied . The LV The same geometrical categories were identified in a study by Andrén and co-workers . As manyIn the LIFE study , a largeA subgroup study of the Framingham heart study  demonstrObesity has been associated with eccentric LVH, while hypertension has been associated with concentric LVH . PersonsA study by Sveälv and co-workers in 2005 demonstrated a significant age-related decrease in end-diastolic and end-systolic volumes which was explained by shortening of the long axis length which resulted in an increased sphericity with age. This remodeling during normal aging appeared to be more pronounced in females .Most of these studies were designed to study the hemodynamic patterns and the remodeling of the left ventricle, but whether there were gender-related differences was not investigated. One of the exceptions was the study by Krumholz and co-workers in which members of the Framingham Heart study and Framingham Offspring Study were investigated . They foHowever we could not find such a difference between the genders in our analysis, probably depending on that our participants were elderly subjects in a general population treated with a great number of CV medications.In the present study we investigated the genders separately and tried to reveal if there were any significant hemodynamic differences between the LV geometrical categories recognized in the earlier studies. Studying the frequency distribution of the four distinguished LV geometrical groups in men vs. women indicated no significant differences. Almost 43 percent of the men and 47 percent of the women had a normal geometry. The most common abnormal geometry was the concentric remodeling group  followed by concentric and eccentric LVH.Thus, the present study differed from Andrén's study  in 70-yeA significant interaction between gender and SBP was found regarding LV geometry groups. However, an increased SBP were seen in women in all LV geometric groups except the eccentric LVH group. This finding does not indicate that women have a different sensitivity to the SBP level for the development of an abnormal LV geometry, since women in the normal LV group also had an elevated systolic blood pressure.The proportion of males and females taking antihypertensive drugs were very similar. However, the systolic blood pressure was significantly higher in woman than in men both in the group on antihypertensive treatment, as well as in the group without any treatment. Therefore, the gender difference does not seem to be due to any difference in blood pressure medication. In this age-group, SBP seems to be generally higher in women than in men. The reason for this is not known, but it is clear that this increased SBP in women is not reflected in any higher prevalence of LVH.Ganau and co-workers presented different hemodynamic patterns in the different LV geometrical categories . ConcentComparing systolic indices, such as EF and CI in men vs. women indicated a significant discrepancy between the genders regarding EF, but no significant difference in CI. However, despite these differences in EF between the genders, possibly due to an increased prevalence of MI in the males, no significant interactions were seen between gender and LV geometry groups regarding LV systolic variables.Andrén and co-workers showed a significant prolongation of IVRT only in the eccentric LVH group and a prolongation of the deceleration time in the concentric LVH group suggesting abnormal relaxation and low LV compliance . Left atIn the present study, the E/A-ratio was significantly lower, LA diameter increased and IVRT longer in all three abnormal categories compared with the normal group, indicating a more severe LV diastolic dysfunction in the present study as compared to the study by Andren et al.Concerning diastolic variables we found a significant difference in LA size and IVRT, but no significance in the E/A-ratio, between men and women. However, despite this gender difference, no significant interactions were seen between gender and LV geometry regarding LV diastolic function.The present sample is an extensive study which investigated more than 1000 individuals consisting of almost the same number of males and females, but it is limited to Caucasians aged 70. So, caution should be made in drawing conclusions about other ethnic and age groups. The present study had a moderate participation rate. However, an analysis of non-participants showed the present sample to be fairly representative of the total population regarding most cardiovascular disorders and drug intake.LV mass and EF were calculated based on M-mode measurements. 3D ultrasound recordings or myocardial MRI might give more appropriate results. Furthermore, since a large number of the subjects were on different CV medications, it cannot be excluded that use of particular types of drugs of combinations thereof might have confounded the results.Alteration of the left ventricle (LV) as a consequence of hypertension is a well known phenomenon and numerous studies have demonstrated that LV hypertrophy is a strong and independent predictor of cardiovascular events.However, differences between the genders in the relationship of hemodynamics to LV geometry are not well known.➢ Although mean values of many echocardiographic variables differed between men and women, the LV geometric adaptations to a given hemodynamic load appear similar in both genders.➢ No significant difference between the genders was observed regarding the prevalence of the LV geometric abnormalities.The authors declare that they have no competing interests.SM: analyzed the data and wrote the manuscript; LL: contributed to the study design and organized the study; LL and JS: revised the manuscript critically for important intellectual content. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/11/25/prepub


Pulmonary hypertension (PH) occurs frequently and results in functional limitation in advanced COPD. Data regarding the functional consequence of PH in less severe COPD are limited. Whether echocardiographic evidence of right sided heart pathology is associated with functional outcomes in patients with non-severe COPD is unknown.We evaluated pulmonary function, six minute walk distance, and echocardiography in 74 consecutive patients with non-severe COPD. We performed multivariable linear regression to evaluate the association between right heart echocardiographic parameters and six minute walk distance adjusting for lung function, age, sex, race, and BMI.The mean six minute walk distance was 324±106 meters. All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.3%±6.1%). 54.1% had evidence of some degree of diastolic dysfunction. 17.6% of subjects had evidence of right ventricular enlargement and 36.5% had right atrial enlargement. In univariate analysis RV wall thickness , log right atrial area , LV mass index , E/E' ratio , and degree of diastolic dysfunction  were associated with six minute walk distance. After adjustment for co-variables, the associations between right atrial area  and right ventricular wall thickness  with lower six minute walk distance remained significant independent of forced expiratory volume in one second (FEV1). LV mass index, E/E' ratio, and degree of diastolic dysfunction were not independent predictors of six minute walk distance.In patients with non-severe COPD right sided cardiac structural changes are associated with lower six minute walk distance independent of lung function. These findings may indicate that echocardiographic evidence of pulmonary hypertension is present in patients with non-severe COPD and has important functional consequences. Chronic obstructive pulmonary disease (COPD) recently surpassed cerebrovascular disease to become the third leading cause of death in the United States, and is the only leading cause of death that is increasing in prevalence Pulmonary hypertension (PH) occurs frequently in patients with advanced COPD and has been associated with decreased exercise capacity and increased mortality independent of degree of impairment in lung function Echocardiography plays an important role in screening for and following the progression of patients with PH Body mass index, degree of Obstruction (FEV1), Dyspnea score , Exercise capacity ) index, echocardiographic parameters, and full pulmonary function testing.We reviewed 74 consecutive patients with clinically indicated echocardiograms and pulmonary function data seen in the Northwestern Asthma and COPD program between July 1, 2006 and April 1, 2010. The Northwestern University Institutional Review Board approved the study and granted a waiver of informed consent. Data collected included general demographic information, six minute walk distance, Modified Medical Research Council (MMRC) dyspnea scores, BODE  was performed in the hospital pulmonary function laboratory by trained technicians according to ATS-ERS standards and guidelines Six minute walk testing was performed in the Northwestern Asthma and COPD clinic by trained technicians according to ATS guidelines Echocardiograms were performed in the clinical echocardiography laboratory using either Philips (ie33) or GE (Vivid7) echocardiography machines. All studies were analyzed and measured using a systematic protocol by a single cardiologist blinded to all other data. Echocardiographic data collected for analysis included: left ventricular (LV) end diastolic dimension, biplane LV end-diastolic volume, biplane LV end-systolic volume, LV mass, LV ejection fraction, cardiac output, left atrial volume, right ventricular (RV) basilar diameter, RV longitudinal dimension, RV end diastolic area, RV wall thickness, RV outflow track diameter, right atrial area, early mitral inflow velocity (E), late mitral inflow velocity (A), early septal diastolic longitudinal velocity (E'), diastolic function grade, peak tricuspid regurgitation (TR) velocity, pulmonary artery systolic pressure, tricuspid annular plane systolic excursion (TAPSE), and RV fractional area change All echocardiographic parameters were measured and calculated according to previously published guidelines Data are presented as mean ± standard deviation or frequency and percent. Univariable and multivariable analyses were performed to evaluate whether echocardiogram parameters or lung function variables predicted six minute walk distance. Comparison of means was done via Student's t tests. Multiple means were compared using analysis of variance (ANOVA) with Bonferroni adjustment for multiple comparisons. The relationships between given parameters and the 6MWD were assessed by univariable and multivariable linear regression. Co-variables included in statistical models were pre-specified based on a known or hypothesized association with exercise tolerance in COPD. Age, sex, height and weight were specifically included as co-variables given their direct impact on six minute walk distance 2. There was no difference in sex, age, or race across levels of COPD severity. The total lung capacity was within normal limits  but the residual volume was elevated . The diffusion capacity for carbon monoxide (DLCO % predicted) was moderately reduced (55.8±18.2%), however oxygen saturation at rest was normal (96.0±2.7%). The mean six minute walk distance was 324±106 meters. The mean six minute walk distance decreased with worsening lung function  but did not meet statistical significance. The mean MMRC dyspnea score was 1.7±1.1, and mean BODE index was 2.4±2.1. Both MMRC  and BODE  increased with worsening lung function but only BODE was statistically significant. (Subjects were predominantly Caucasian (72.2%) and had a mean age of 72±11 years and a body mass index of 27.8±6.0 kg/mificant. Table 12) were within normal limits. However, approximately 17.6% of subjects had evidence of right ventricular enlargement 2) with 36.5% of subjects demonstrating evidence of right atrial enlargement Full assessment of right heart dimensions was available in all 74 subjects. The mean right ventricular basilar diameter (3.7±0.5 cm), right ventricular longitudinal dimension (7.7±0.9 cm) and right ventricular end diastolic area (23.7±4.5 cm2) and end diastolic (36.7±7.1 mL/m2) volume indices were within normal limits. The left ventricular mass index was normal in both males (74.1±19.9 g/m2) and females (68.2±20.7 g/m2). The left atrial volume indices were at the upper limits of normal for both males (29.4±13.1 mL/m2) and females (27.6±10.9 mL/m2). There was no clinically significant difference in either LV structural parameters or LV function when compared across degrees of COPD severity. (2 and 33.3% (5/15) had right atrial enlargement with right atrial area greater than 18 cm2. The RV wall thickness was within normal limits in all patients with normal diastolic function. The degree of diastolic dysfunction was not associated with extent of COPD severity.  and preserved cardiac output . The left ventricular end systolic  and RV basilar diameter  both correlated with pulmonary artery systolic pressure. The right atrial area  and RV end diastolic area  both trended toward an association but did not reach statistical significance. Markers of LV diastolic function did not correlate with RV parameters as strongly as PASP: E/A ratio was not correlated with RV end diastolic area , right atrial area  or RV wall thickness . E/E' ratio likewise showed no correlation with RV end diastolic area  or right atrial area  but did correlate with RV wall thickness . Figure 1An evaluation of the association between cardiac function and structural changes on echocardiogram and six minute walk distance independent of lung function impairment was performed using multivariable linear regression. Significant correlations were noted between the six minute walk distance and both right atrial area  and right ventricular wall thickness . Figure 2No association was seen between the echocardiogram parameters and MMRC dyspnea score or the integrative BODE index (data not shown).We report our experience with cardiac structural changes and their association with patient- centered outcomes in 74 consecutive patients with mild, moderate, or moderately severe COPD. In this cohort of patients without severely impaired lung function we demonstrated that structural changes of the right heart are associated with a decrement in six minute walk distance. This association was independent of the severity of COPD as measured by FEV1 as well as age, sex, race and body mass index. We did not find an association between six minute walk distance and right ventricular function as assessed by TAPSE or left ventricular systolic or diastolic function. This is the first report to our knowledge of right heart structural changes suggestive of pulmonary hypertension in patients with non-severe COPD being linked to a patient-centered functional endpoint. This report is consistent with our findings that pulmonary hypertension of any cause has important functional consequences in patients with advanced COPD, but extends this finding to patients with less severe disease Pulmonary hypertension is a well described comorbidity in advanced COPD. In a study of close to 5000 patients with advanced COPD awaiting lung transplant, using the standard definition for pulmonary arterial hypertension  exhibited some degree of diastolic dysfunction. Although it is clear that the right heart structural changes seen in this study are independent of LV systolic function, without right heart catheterization it is difficult to differentiate if the changes are related to LV diastolic dysfunction or primary pulmonary vascular disease. It is interesting to note that structural changes of the right heart were present in the subset of patients with both normal left ventricular systolic and diastolic function. Unfortunately, the total number of observations (n = 15) is too small to draw conclusions related to their impact on outcomes in this subset of subjects. In advanced COPD the functional impact of pulmonary hypertension appears to be independent of the distinction between PH related to pulmonary vascular disease and PH related to diastolic heart failure. The mean pulmonary artery pressure has been shown to be associated with a lower six minute walk distance independent of the left heart filling pressures which likely drive pulmonary hypertension related to diastolic heart failure. Furthermore, both primary pulmonary vascular disease and pulmonary venous hypertension related to diastolic heart dysfunction impacted survival of patients with COPD on the lung transplant list compared to those with normal hemodynamics There are a number of limitations to our study. Since echocardiography was used instead of cardiac catheterization it is not possible to clearly distinguish whether these patients had PH related primarily to pulmonary vascular changes or PH related to left heart disease such as left ventricular diastolic dysfunction. However, the association between right heart structure and six minute walk distance remained independent of LV systolic and diastolic dysfunction. These multivariable regression analyses suggest that right heart structural changes, above and beyond that due to left heart disease may be playing a role in limiting exercise capacity in non-severe COPD. Furthermore, previous data have shown that although the distinction between pulmonary arterial and pulmonary venous hypertension is likely important when making therapeutic decisions, the functional implications of PH in COPD may be independent of the underlying cause of PH In conclusion, we demonstrated that in subjects with non-severe COPD right heart structural changes are associated with reduced six minute walk distance. Early identification of right heart structural changes in COPD may result in identification of a specific COPD phenotype which is associated with reduced exercise capacity. This is consistent with prior reports of PH in advanced COPD having distinct prognostic and functional implications. Identification of cardiac structural changes in patients with COPD that are associated with patient centered outcomes may lead to novel therapeutic targets to impact a specific disease phenotype.


Remodeling of the left ventricle (LV) occurs in response to various physiological and pathophysiological conditions. The American Society of Echocardiography recommend that LV remodeling be described as the relationship between LV mass and LV wall thickness based on 1-D and 2-D measurements. Cardiac magnetic resonance (CMR) provides accurate 3-D measures of LV volumes and mass; however, there is no universally agreed upon approach to measure remodeling. We propose using the ratio of LV mass to LV end-diastolic volume (LVEDV) as the left ventricular remodeling index (LVRI).To describe and compare patterns of LV remodeling in various cardiac conditions using CMR. We hypothesized that the LVRI would accurately reflect underlying pathophysiology.A total of 105 consecutive cases , with elevated LV mass  from 2006-2009 were obtained from the CMR clinical database at our institution. 32 healthy volunteers served as controls. Based on the clinical history and the qualitative CMR findings, cases were categorized as: inflammatory (INF), dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), pressure loaded (PL) (eg. aortic stenosis and systemic hypertension) and volume loaded (VL) .Quantitative volumetric analyses were performed using standard imaging analysis software . A short axis stack of steady state free precession cines were used to obtain LV mass and LVEDV by methods of disks. The LVRI was calculated from the ratio of LV mass to LVEDV. Statistical significance was assessed using an unpaired Student’s T-test.The DCM, ICM and PL groups were significantly older and the INF group had a greater proportion of males compared to controls. There was no statistically significant difference in LVRI between males and females or between older (age >35) and younger adults.The mean LVRI for controls was 0.87±0.1g/ml. Compared to controls, mean LVRI was elevated in INF  and PL (0.98±0.12g/ml p=0.002). Conversely, mean LVRI was reduced in ICM  and VL . There was no statistically significant difference in mean LVRI between DCM and controls. Table LVRI is a simple method for quantifying in a variety of cardiac conditions. The observed values reflect underlying pathophysiology, with elevated indices in myocardial edema or increased afterload, and decreased indices with LV wall infarction or increased preload. Future studies should assess its role in the serial assessment of ventricular geometry and at earlier stages of disease.


Although the maze procedure is an established surgical treatment for eliminating atrial fibrillation (AF), its efficacy in patients with mitral valve disease has remained unsatisfactory. A useful predictive marker for the outcome of the maze procedure is needed. The aim of this study was to investigate whether the preoperative ratio of atrial natriuretic peptide (ANP) to brain natriuretic peptide (BNP) reflects atrial fibrosis and can be used to predict the maze procedure outcome in patients with mitral valve disease.A total of 23 consecutive patients who underwent the radial approach to the maze procedure combined with mitral valve surgery were included in this study and were divided into a sinus rhythm (SR) group (n=16) and an AF group (n=7) based on postoperative cardiac rhythm. Plasma samples were obtained at rest before the operation and were analysed for ANP and BNP levels. Atrial tissue samples taken during surgery were used to quantify interstitial fibrosis.The preoperative ANP-to-BNP ratio in the SR group was significantly higher than that in the AF group . Receiver operating characteristic (ROC) curve analysis was used to identify factors that predict outcomes after the maze procedure. The area under the ROC curve for the ANP-to-BNP ratio (0.81) was greater than for any other preoperative factors. Moreover, the preoperative ANP-to-BNP ratio demonstrated a negative correlation with left atrial fibrosis .The preoperative ANP-to-BNP ratio can predict maze procedure outcome in patients with mitral valve disease, and it represents a potential biomarker for left atrial fibrosis. Atrial fibrillation (AF) is the most common cardiac arrhythmia, especially for patients with mitral valve disease. The presence of postoperative AF is a significant risk factor for postoperative mortality, stroke, and other thromboembolism and anticoagulant-related haemorrhage . TherefoAtrial fibrosis plays an important role in developing and maintaining AF. Yoshihara et al. reported that the collagen volume in left atrial tissue was higher in AF than in SR . HoweverIn the present study, we hypothesized that the preoperative ANP-to-BNP ratio more accurately predicts the outcome of a maze procedure in patients with mitral valve disease than the known risk predictors. Furthermore, we evaluated the ANP-to-BNP ratio as a biomarker for atrial interstitial fibrosis, which is a pathological process that has been associated with AF.A total of 23 consecutive patients who had mitral valve disease  and AF and underwent the radial approach to the maze procedure  at YamagBlood samples were taken at rest before the operation. Plasma ANP concentration was measured with a chemiluminescent enzyme immunoassay for α-human ANP  as previously described . Plasma We examined interstitial fibrosis samples from the left atrium, left atrial appendage, right atrium and right atrial appendage of 16 patients in this study. The quantitative collagen assay  was performed as previously described . In briet-test and Fisher’s exact test. The unpaired t-test was used for continuous variables with normal distribution. Fisher’s exact test was used for categorical variables. Receiver operating characteristic (ROC) curve analysis was used to identify factors that predict the outcomes of a maze procedure. Associations between continuous variables were assessed using correlation and linear regression techniques. P<0.05 was considered significant.Continuous data with was expressed as mean ± standard deviation. Categorical variables were reported as frequencies. Pre- and postoperative data were analysed using the unpaired To elucidate a predictive factor for maze procedure outcome, we compared preoperative variables between the SR n=16) and AF groups (n=7). There were no significant differences in age, gender, CTR, left ventricular end-diastolic dimension (LVDd), ejection fraction (EF) and the preoperative ANP and BNP levels between two groups. In contrast, there was significant difference in LAD and the preoperative ANP-to-BNP ratio between the two groups . The preoperative ANP-to-BNP ratio was not identified as an independent factor by the multivariate analysis (p=0.059), but compared to the other factors, the ANP-to-BNP ratio demonstrated the most significant difference  for CTR and LAD was 0.79 and 0.75, respectively, indicating that CTR and LAD are also useful predictors of the outcome of a maze procedure, which is consistent with previous reports. Here, we found that the AUC for the preoperative ANP-to-BNP ratio was 0.81 or higher than AUC for ANP or BNP levels Figure . FurtherNext, we investigated the correlation between the preoperative ANP-to-BNP ratio and atrial fibrosis. Figure We also observed that left atrial fibrosis (%) in the AF group was significantly higher compared to that in the SR group (AF group, 8.7 ± 2.4%; SR group, 6.2 ± 1.2%; p=0.014, Figure This is the first demonstration of a relationship between the preoperative ANP-to-BNP ratio and maze procedure outcome in patients with mitral valve disease. Atrial remodelling is important in maintaining AF. Intra-atrial conduction block, which leads to small and numerous reentrant circuits, is caused by increased atrial fibrosis ,17. The We have also found that the preoperative ANP-to-BNP ratio is correlated with left atrial fibrosis. Although increased left atrial fibrosis is thought to be associated with the progression of mitral valve disease and failure of the maze procedure, the role of left atrial fibrosis in the development, recurrence and persistence of AF has not been fully elucidated. Saito and colleagues reported a correlation between the postoperative recurrence of AF and fibrosis in the left atrial appendage . KataokaCurrently, the precise mechanism by which the preoperative ANP-to-BNP ratio is negatively correlated with left atrial fibrosis remains unknown. ANP is produced, stored and released by atrial cardiomyocytes in response to atrial stretch. It has been also reported that the decrease in plasma ANP is caused by the progression of atrial fibrosis . This suThis study has some limitations. Although we observed a significant correlation between the preoperative ANP-to-BNP ratio and maze procedure outcome, the sample size was quite small. Further studies with larger sample sizes are needed to establish the usefulness of the preoperative ANP-to-BNP ratio. We assessed the cardiac rhythm by electrocardiography in 21 patients and by 24-hour electrocardio-monitoring in the remaining 2 patients. Therefore, the success rate after the maze procedure may be overestimated. In a previous study, when the use of electrocardiography was compared with 24-hour electrocardio-monitoring, the detection rate of AF recurrence differed by 5.5%. However, the difference was not statistically significant . It has In conclusion, our findings demonstrate that the preoperative ANP-to-BNP ratio correlates negatively with left atrial fibrosis, predicts the outcome of a maze procedure in patients with mitral valve disease and represents a new biomarker that helps to decide when to perform a maze procedure.The authors declare that they have no competing interests.MS developed study protocol, obtained data, analyzed data and wrote manuscript. AM developed the study protocol and provided critical revision of the manuscript. HK, RS, MM, TK, KY, and KH provided critical revision of the manuscript. All authors read and approved the final manuscript.


During rapid filling of the left ventricle, a vortex ring forms downstream from the mitral valve. Previous experiments in water tanks have shown that vortex ring formation is an optimized method for fluid transport. The rotation of the vortex ring leads to mixing of the inflowing blood and blood that was already in the ventricle Figure . In wateNine healthy volunteers and four patients with dilated ischemic cardiomyopathy underwent cardiovascular magnetic resonance including 4D PC-MRI. Particle tracing was used to track blood flowing into the left ventricle during rapid filling Figure . Lagrang3.VFR was computed as follows: End-systolic volume (ESV) and the volume of the left ventricle at diastasis  were measured by manual delineations in short-axis cine images. E-wave volume (EWV) was computed as DV-ESV. The diameter of the mitral valve D was measured as the average of the diameters in the three-chamber view and perpendicular to the three-chamber view in the short-axis view. VFR was computed as VFR = 4/π×EWV/DThe mixing fraction was significantly higher in the patients compared to the volunteers . In contrast to previous studies in water tanks, there was no significant correlation between VFR and the mixing ratio in either group Figure .We found a higher mixing ratio in the patients compared to the healthy volunteers. The absence of a significant correlation between VFR and mixing fraction suggests that vortex ring formation in the left ventricle of the human heart is subject to additional complexity and asymmetry compared to experimental studies in water tanks.This study was supported by Swedish Research Council grants VR 621-2005-3129, VR 621-2008-2949 and VR K2009-65X-14599-07-3, National Visualization Program and Knowledge Foundation grant 2009-0080, the Medical Faculty at Lund University, Sweden, the Region of Scania, Sweden and the Swedish Heart-Lung Foundation.SJK is supported in part by the Alan A. and Edith L. Wolff Charitable Trust, St. Louis, MO, USA, and the Barnes-Jewish Hospital Foundation, St Louis, MO, USA.


Cardiac auscultation has been the central clinical tool for the diagnosis of valvular and other structural heart diseases for over a century. Physicians acquire competence in this technique through considerable training and experience. In Africa, however, we face a shortage of physicians and have the lowest health personnel-to-population ratio in the world. One of the proposed solutions for tackling this crisis is the adoption of health technologies and product innovations to support different cadres of health workers as part of task shifting.Computer-assisted auscultation (CAA) uses a digital stethoscope combined with acoustic neural networking to provide a visual display of heart sounds and murmurs, and analyses the recordings to distinguish between innocent and pathological murmurs. In so doing, CAA may serve as an objective tool for the screening of structural heart disease and facilitate the teaching of cardiac auscultation. This article reviews potential clinical applications of CAA. Prior to the development of echocardiography and other imaging modalities, the stethoscope was the central investigative tool for the diagnosis of structural heart disease. While the stethoscope is relatively inexpensive and widely available, it remains a qualitative and subjective method of evaluating heart sounds, murmurs and other cardiac noises. The development of the digital stethoscope with additional analysis software promises to transform the stethoscope into a tool for quantitative and objective clinical evaluation of the heart. Such a tool may improve the assessment of innocent murmurs, reduce observer variation due to human acoustic abilities, and facilitate the teaching of cardiac auscultation.Up to 80% of paediatric patients have a cardiac murmur, although less than 1% will eventually have a pathological condition underlying the murmur.The innocent murmur is, however, the most frequently misdiagnosed condition when testing auscultation skills of medical practitioners.4Echocardiography is the first-line imaging modality for the confirmation of a diagnosis of structural heart disease.6These guidelines discourage the indiscriminate use of echocardiography as a screening tool due to the cost and the potential for overdiagnosis of disease. Despite this, patients are still referred inappropriately for echocardiography for the evaluation of innocent murmurs. In a retrospective review of 3 460 adult referrals for echocardiogram with the coding ‘murmur’ as the primary reason for referral, less than 50% had significant valvular disease.There is therefore a major need to improve the ability of medical practitioners to identify murmurs that have a high probability of structural heart disease. CAA promises to address this need by providing a decision support tool on the likelihood of the presence of pathological murmur.In the past decade, numerous reports have expressed concern over the training of healthcare professionals in cardiac auscultation.The ability of a digital stethoscope to record sounds, replay them at different speeds, provide a visual display and develop a database of heart sounds for on-going review creates a unique vehicle for teaching auscultation and is a major incentive for the addition of CAA into current teaching programmes.The pursuit of a quantitative and objective stethoscope has occupied investigators for decades, and electronic stethoscopes have been available commercially for some time.13The CAA provides a spectral and temporal analysis of heart sounds and a graphic display of the energy profiles relating to systolic and diastolic murmurs The Food and Drug Administration (FDA) has approved the first CAA system as an aide to the physician for the detection of abnormal heart murmurs. Using this software, the sensitivity for detection of murmurs increased from 77 to 89%, while the referral sensitivity increased from 87 to 93% among primary-care physicians.18CAA is a promising decision support tool for the identification of pathological murmurs and appropriate referral of cases for further investigation. Primary-care physicians assessing asymptomatic patients with heart murmurs were able to increase the sensitivity of pathological murmurs detected with the use of CAA from 77 to 89%, while referral sensitivity increased from 87 to 93%, and specificity increased from 64 to 79%.16The clinical utility of the digital stethoscope and associated software in detecting cardiac disease has great potential The need for a method to detect athletes at risk of sudden cardiac death due to hypertrophic obstructive cardiomyopathy led to a pilot study examining the level of agreement between auscultation by a cardiologist and the results of CAA.The third heart sound is an early abnormality in adult patients with heart failure. It is frequently missed in a cursory examination of the heart, but is easily recorded by means of CAA.21The most common cause of acquired heart disease in the world, rheumatic heart disease, has long been neglected due to its waning incidence in the developed world.24Co-existing cardiovascular disease during pregnancy is a leading cause of maternal mortality and contributes to significant morbidity.A recent World Health Organisation report outlined the crisis in human resources in healthcare, and focused on the particular shortage of trained specialists in sub-Saharan Africa.29A key issue regarding the health worker shortage in sub-Saharan Africa is insufficient training opportunities. Two-thirds of sub-Saharan African countries have only one medical school, and 11 sub-Saharan African countries have no medical school at all.Another use of CAA is in the field of telemedicine. Recording heart sounds using a digital stethoscope and transmitting the sound data for remote assessment by a cardiologist was demonstrated to have a sensitivity and specificity of 90 and 98%, respectively, for the detection of pathological murmurs, with low inter-observer and intra-observer variability.32Despite the potential of CAA, it has yet to be adopted into mainstream clinical practice. There are several factors which may improve the chances of adoption of this new technology.Finally, single-praecordial-site CAA does not approximate the clinical routine of auscultation in different sites, use of diaphragm, bell and adjunct manoeuvres to comprehensively examine the heart. A new recording device using a multiple-praecordial-site approach, simultaneously acquiring six auscultation sites, a single-channel ECG and a respiratory recording, is under development.Heart disease is a major cause of morbidity and mortality in all age groups worldwide. For decades, conventional auscultation has been the mainstay for screening and diagnosis of structural heart disease. However, the inherent limitations of the standard stethoscope have resulted in declining reliance on auscultation findings and the inappropriate referral for echocardiography of large numbers of patients with innocent murmurs.CAA provides objectivity to a traditionally subjective clinical skill. As an objective diagnostic support tool, it may improve the number of appropriate cases of murmur that are referred for echocardiography from primary care. Furthermore, CAA can provide a new platform for teaching cardiac auscultation to health science students and physicians. Finally, CAA may provide a decision support tool for mid-level and community health workers, with linkage to central expertise and training through telemedicine.


The dual-bolus protocol enables accurate quantification of myocardial blood flow (MBF) by first-pass perfusion cardiovascular magnetic resonance (CMR). However, despite the advantages and increasing demand for the dual-bolus method for accurate quantification of MBF, thus far, it has not been widely used in the field of quantitative perfusion CMR. The main reasons for this are that the setup for the dual-bolus method is complex and requires a state-of-the-art injector and there is also a lack of post processing software. As a solution to one of these problems, we have devised a universal dual-bolus injection scheme for use in a clinical setting. The purpose of this study is to show the setup and feasibility of the universal dual-bolus injection scheme.The universal dual-bolus injection scheme was tested using multiple combinations of different contrast agents, contrast agent dose, power injectors, perfusion sequences, and CMR scanners. This included 3 different contrast agents , 4 different doses , 2 different types of injectors (with and without "pause" function), 5 different sequences (turbo field echo (TFE), balanced TFE, k-space and time (k-t) accelerated TFE, k-t accelerated balanced TFE, turbo fast low-angle shot) and 3 different CMR scanners from 2 different manufacturers. The relation between the time width of dilute contrast agent bolus curve and cardiac output was obtained to determine the optimal predefined pause duration between dilute and neat contrast agent injection.161 dual-bolus perfusion scans were performed. Three non-injector-related technical errors were observed (1.9%). No injector-related errors were observed. The dual-bolus scheme worked well in all the combinations of parameters if the optimal predefined pause was used. Linear regression analysis showed that the optimal duration for the predefined pause is 25s to separate the dilute and neat contrast agent bolus curves if 0.1 mmol/kg dose of Gd-DO3A-butrol is used.The universal dual-bolus injection scheme does not require sophisticated double-head power injector function and is a feasible technique to obtain reasonable arterial input function curves for absolute MBF quantification. First-pass myocardial perfusion cardiovascular magnetic resonance (CMR) uses a series of T1-weighted images during the passage of a contrast bolus through the heart to characterize myocardial blood flow (MBF). The use of fully quantitative analysis of first-pass myocardial perfusion CMR allows the absolute quantification of MBF in units of ml/min/g and may permit an accurate, objective assessment of altered myocardial perfusion in patients with heart disease (1-3). Accurate MBF quantification by myocardial first-pass perfusion CMR relies on a linear relationship between signal intensity and gadolinium concentration. However, it is well-known that with gadolinium concentrations currently in use for first-pass perfusion MR imaging, T1-saturation effects can cause substantial signal attenuation predominantly in the left ventricular (LV) cavity where the signal intensity-time curve usually represents the arterial input function (AIF) . To preserve an accurate AIF, previous studies using quantitative measures have focused on low doses (0.025 mmol/kg-0.05 mmol/kg) of contrast agent in combination with strongly T1 weighted sequences. Low-dose techniques are applied for precise and reproducible absolute quantification of cardiac perfusion. However, this approach is limited by a low contrast to noise ratio (CNR) in the myocardial tissue as a result of limited myocardial enhancement.To overcome the limitation of T1-induced MR signal saturation in the LV blood pool and low CNR in the myocardial tissue, dual-bolus first-pass perfusion CMR methods were recently introduced to allow the use of high gadolinium concentration contrast for myocardial analysis, and a lower gadolinium concentration bolus to maintain the linearity of the LV signal intensity (6-10). These techniques use a low dose of dilute contrast agent as a prebolus before the main bolus of neat contrast agent.Clinically important issues in the dual-bolus protocol are that:1) Both the main-bolus of neat gadolinium contrast agent (CA), and the pre-bolus of diluted gadolinium CA solution, should be of equal volume and administered at the same flow rate.2) Each bolus should be followed by a saline flush to maintain a compact CA bolus in the LV chamber. Each bolus should also be equal in volume and administered at the same rate(6-9).3) The time delay between each bolus of CA can be controlled to minimize temporal overlap, this delay can be also adjusted to heart rate if required(6-8),4) The system should be easy to set up5) The procedure is easy to perform and repeat within a routine clinical scan.The dual-bolus protocol enables accurate quantification of MBF by first-pass myocardial perfusion CMR (9). However, despite the advantages and increasing demand for the dual-bolus method for accurate quantification of MBF(11), thus far, it has not been widely used in the field of quantitative perfusion CMR. The main reasons for this are that the setup for the dual-bolus method is complex and requires a state-of-the-art injector and also there is a lack of post processing software. As a solution to one of these problems, we have devised a universal dual-bolus injection scheme that does not require a sophisticated double-head power injector and can be easily employed in a clinical setting. The purpose of this study is to show the set-up and feasibility of the universal dual-bolus injection scheme.The set-up for the universal dual-bolus injection scheme is described as a step-by-step protocol as follows.For injectors with a programmable "pause" functionality   Figure 1. Draw 1 ml of gadolinium CA into a 10 ml syringe (syringe 1) and dilute it to a 10% solution by adding 9 ml of saline. Repeat this process for syringe 2.2. Adjust the volume of syringe1 and syringe 2 according to the weight of the patient i.e. if a 60 kg patient needs 6 ml of 1.0 mol/L gadolinium CA then discard 4 ml of CA from 10 ml syringe (syringe 1 and 2 therefore consist of 10% dilute gadolinium CA).3. Draw the same volume of neat gadolinium CA into two additional 10 ml syringes (syringe 3 and 4 therefore consist of neat gadolinium CA).Note: These two pairs of syringes containing 10%-dilute and neat gadolinium CA are used for the stress and rest bolus injection respectively. It is possible to substitute larger or smaller syringes adapted to the dose of contrast medium. All syringes should be carefully labelled.Step 2 (Preparation of injector and tubing)  Figure  and 2A1. Fill both the first (A) and second (B) power injector syringes with at least 60 ml of saline.2. Connect Y-shaped long tube to injector syringes as per the manufacturer's instructions.3. Connect a three-way stopcock (stopcock A) to the distal end of the Y-shaped long tube.4. Connect a high-pressure extension tube with 15 ml volume to stopcock A.5. Flush these tubes with saline6. Connect the distal end of the high-pressure extension tubes to a venous cannula in the patient's antecubital vein.Step 3   Figure .1. Injector A (first phase): Set the flow rate to 4 ml/s and the volume of saline flush to 25 ml).2. Injector A (second phase): To program the delay time between the pre-bolus and the main-bolus, use the "pause" phase and set the desired time delay.3. Injector B: Set the flow rate and volume of the saline injection as for injector A.Step 4 1. Connect the 10 ml syringe containing dilute CA (syringe 1) to stopcock A without injecting the CA Figure .2. Once the set up for the perfusion scan is ready, arm the injector.3. Just prior to the power injection turn stopcock A and manually inject the entire volume of dilute CA (syringe 1) into the high-pressure extension tube Figure  and 1D.4. Disconnect the syringe 1 (dilute CA) and connect the 10 ml syringe containing neat CA (syringe 3) to stopcock A without injecting the CA Figure .5. Start the perfusion scan and the power injection at the same time.6. During the delay time, turn stopcock A and manually inject the entire volume of neat CA from the syringe 3 (neat CA) into the high-pressure extension tube.7. After the programmed delay, injection B  starts. This allows the contrast agent within the extension tube to be pushed into the patients Figure .For injectors with no programmable "pause" functionality   Figure 1.-3. All steps as described above.Step 2 (Preparation of injector and tubing)Figure  and 4A1. Fill both the first (A) and second (B) power injector syringes with at least 60 ml of saline.2. Connect a three-way stopcock (stopcock B) to the tip of syringe A. This enables the attachment of a syringe to act as a release mechanism for the additional saline injection, which is programmed to allow a delay between dilute and neat CA. Connect the empty 10 ml syringe to stopcock B Figure  and 4A. 3. -6. These steps as described above.Step 3 Figure .1. Injector A (first phase): Set the flow rate to 4 ml/s and the volume of saline flush to 25 ml.2. Injector A (second phase): As this injector does not have a "pause" function, we need to set the flow rate and volume of the saline injection, which will allow a specific time delay. For example, for a 10s delay, 1 ml volume at 0.1 ml/sec, for a 15s delay, 3 ml volume at 0.2 ml/sec, for a 20s delay, 2 ml volume at 0.1 ml/s etc. This additional saline will then be taken up into the "release" syringe, thereby ensuring that there is no dilution of contrast agent, which will be injected into the extension tube during the delay.3. Injector B: Set the flow rate and volume of the saline injection as for injector A.Step 4 1. -6. These steps as described above Figure .7. Just after injection A is completed Figure , turn st8. -9. These steps as described above Figure .During dynamic CMR image acquisition the patient is instructed to breath gently as the first bolus is delivered via the power injector and during the pause. The patient is subsequently instructed to hold their breath whilst the main bolus is delivered. Consequently each CA bolus, of equal volume, is delivered to the patient at the same flow rate with a pre-programmed temporal delay between the dilute and neat bolus. A second dual-bolus perfusion CMR acquisition can be performed by repeating step 3 and step 4.®, Schering, Germany) (1.0 mol/L). In this setting, the volume of gadolinium CA required is less than 10 ml for an average-sized individual. We, therefore, use 10 ml small syringes and 15 ml extension tubes for the set-up described in this article. However, with minor modifications , this scheme can be applied to any type and dose of commonly used commercially available gadolinium CA.The volume of CA required for this method depends on which particular CA is used (0.5 mol/L or 1.0 mol/L) and on the desired dose of gadolinium CA. The dose of gadolinium contrast agent is adjusted to the patient's weight. The current injection scheme has been developed for a 0.1 mmol/kg dose of Gd-DO3A-butrol , Gd-DTPA  and Gd-DOTA ), 4 different doses , 2 different injectors  and 3 different MR scanners from 2 different manufacturers  were tested /turbo fast low-angle shot (TurboFLASH), balanced TFE, k-space and time (k-t) accelerated TFE and k-t accelerated balanced TFE Table . In addiTo test the feasibility of the dual-bolus set-up, we sent a description of this dual-bolus method  to 3 different sites in different countries and asked them to perform perfusion scans in 5 patients using these methods and predefined pause of 25s.dilute start), dilute peak point (T dilute peak) and dilute end point (T dilute end). T dilute end was specified the time point as; (T dilute peak- T dilute start) + T dilute peak. The time width of dilute CA bolus curve (TW dilute) was defined as T dilute end - T dilute start .Adenosine stress and rest perfusion CMR images were analyzed using dedicated software . On a representative image from the dynamic series, an observer manually placed a circular region of interest (ROI) in the LV blood pool depicted on a basal slice to obtain the time-signal intensity plot of the arterial input function. The ROI was then copied to the other dynamic images of the same slice, the positions reviewed and manually adjusted to correct for respiratory motion during data acquisition if required. In the time-signal intensity plot Figure , we defit Figure . If TW ddilute using MedCalc, version 11.4, software . For all continuous parameters, results are given as the mean ± standard deviation. A p value of less than 0.05 was considered as statistically significant.Linear regression analysis was performed in the 36 patients who underwent stress and rest dual bolus perfusion scan using 0.1 mmol/kg of Gd-DO3A-butrol (1 mol/L) to evaluate the correlation of cardiac output and TW 130 dual-bolus perfusion scans were performed in 70 patients at the original site where the dual-bolus scheme was devised. 31 scans in a further 16 patients were subsequently completed at 3 different sites. In total 161 dual-bolus perfusion scans were performed, 41 (25%) of these were performed using a dual-head power injector with a "pause" function. Three technical errors (1.9%) were observed in the 161 perfusion scans. Two of three errors were observed at the original site. In these two cases, the dilute contrast was confused with neat one resulting in the neat bolus being administered first. The remaining error was observed at a remote site, the most likely cause was related to manual injection of dilute contrast into the extension tube at a wrong time. No power injector related errors were observed. Apart from these 3 errors, all dual-bolus perfusion scans were successfully completed. The preparation time for the dual-bolus set-up was 6.9 ± 1.5 min.For all patients, EF and heart rate at rest and during stress were 57 ± 15% (range 81-16%), 68 ± 13 beat/min (range 43-106 beat/min) and 90 ± 17 beat/min (range 48- 167 beat/min), respectively. Cardiac output was 5.6 ± 1.5 L/min (range 9.6-2.4 L/min) at rest and 7.4 ± 2.1 L/min (range 3.4-14.0 L/min) during stress.dilute and cardiac output  .Linear regression analysis showed a moderate correlation between TW ) Figure . This plThe dual-bolus scheme worked well if the appropriate predefined pause was selected for any of the following conditions: three different contrast agents , 4 different doses , 2 different types of injectors (with and without "pause" function) and 3 different MR scanners from 2 different manufacturers   and 5 patients with low LV function (EF < 30%) in this study patient population . Recently we have proposed an isolated perfused pig heart model for novel sequence development(13). This model is well controlled, offers exact titration of coronary blood flow and has also proven amenable for perfusion imaging using the dual bolus contrast injection scheme. The particular advantage of the pig heart model is that one can perform multiple perfusion scans in a single heart. It is considered an important vehicle for validation of various approaches for quantification of myocardial blood flow before translating those methods to patients. Ritter et al quantified stress and rest MBF by perfusion CMR in healthy volunteers with the pre-bolus technique (14). However, practically the pre-bolus technique requires a different set up because this technique uses 1 ml of undiluted contrast medium for the first bolus to determine the arterial input function. This pre-bolus technique also requires different post processing to construct the AIF from the pre-bolus time-intensity curve. There is only a single study by Utz et al. which applied a dual-bolus technique to stress and rest perfusion CMR in patients (9). However, although they demonstrated improved accuracy for absolute MBF values compared to the single-bolus approach, the details of the dual-bolus injection scheme are not provided. Thirdly, this dual-bolus injection scheme can be performed without any new, unusual or expensive materials or techniques. The only material required in addition to the normal set-up are extension tubes, 3-way stopcocks and syringes which are all widely available.The regression analysis obtained in this study suggested that optimal predefined pause duration between the dilute and neat gadolinium injection is 25 seconds or more if a contrast agent with high gadolinium concentration (1 mol/L) is used. Cardiac output had a negative but only moderate correlation with time width of the dilute CA curve and the time width of the dilute CA curve was significantly longer in the resting state than during stress. These finding suggest that the predefined pause should be prolonged for the rest perfusion scan if there was any overlap of the curves at stress. Theoretically, using a lower concentration of gadolinium contrast agent (e.g. 0.5 mol/L), the bolus profile should be wider than in the case of higher concentration of gadolinium contrast agent (e.g. 1.0 mol/L) because the weight dependent volume of contrast agent given to the patient is larger . Therefore, a longer pause between the two injections should be used.The current approach requires substantial "user" interaction. In the present study, there were 3 technical errors, in two cases the dilute gadolinium agent and the neat contrast agent syringes were confused. A repetition of these errors was avoided by carefully labelling each syringe. Another error was observed at a remote site and related to the manual contrast injection at a wrong time. This occurred during one of the first studies and might be explained by relative inexperience with the method. Undergoing some simple and brief training before applying our methods during clinical scanning should overcome such "user" related problems. This dual-bolus injection scheme requires 6.9 ± 1.5 minutes for the preparation of gadolinium contrast agent and the set-up for power injector and lines. However, the perfusion scan is only extended by the duration of the predefined pause (i.e. ~25s in each perfusion scan). In our institute, standard stress-rest myocardial perfusion CMR set-up with normal single bolus injection scheme requires 3.2 ± 1.8 minutes for the preparation of gadolinium contrast agent and the set-up for power injector and lines. The dual-bolus injection scheme needs just a few more minutes on top of the normal set-upIn patients with low LV function (EF < 30%), the dual-bolus curves tend to overlap due to low cardiac output. In these cases, a longer predefined pause is required. Further investigation is required to ascertain whether the poor bolus profile in these patients still provides diagnostic and accurate MBF quantification. In contrast, our dual-bolus scheme worked well in a patient with LV EF of > 80%.Only adenosine was tested as a pharmacological stress agent in the present paper. Recently, the Food and Drug Administration approved regadenoson for stress testing in conjunction with myocardial perfusion imaging(15). Regadenoson, unlike adenosine, is a selective A2A agonist that is given as an intravenous bolus at a fixed dose and causes myocardial blood flow and heart rate to peak shortly after injection followed by a slow reduction in myocardial blood flow and a decreasing heart rate after approximately 2 minutes. Potentially, this dual-bolus scheme can be applied to regadenosone if the timing of bolus injection of contrast agent and regadenosone is optimized. Further studies will be required to show that this practical dual-bolus approach works for this new vasodilator stress agent.We would like to acknowledge the main limitation of this study. Inevitably the use of a manual contrast injection necessitates the presence of a physician within the MR scanner room at the time of injection. However, the presence of a physician is reassuring for the patient particularly during the stress perfusion.We have devised a universal dual-bolus injection scheme, for use in a clinical setting, that is independent of sophisticated double-head power injector function. The universal dual-bolus injection scheme is a feasible technique to obtain a reasonable arterial input function curve to calculate absolute quantification of myocardial blood flow.EN received major grant support from Philips Healthcare and Bayer Schering Pharma. The other authors declare that they have no competing interests'.MI designed the study protocol, carried out the CMR studies, analyzed the data and drafted the manuscript. AS, GM, AC, SH, MP, NM, HS, DL, BS, KA and SP helped to perform the MR studies and to draft the manuscript. EN designed the study protocol and drafted the manuscript. All authors read and approved the final manuscript.


Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis of the skin and internal organs, including the heart. Traditional late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) imaging is dependent on differential  fibrosis within the myocardium. However, diffuse interstitial myocardial fibrosis (DF) affecting the entire myocardium may be missed because no normal reference region exists. T1 mapping has been utilized in a variety of techniques to assess diffuse fibrosis: 1) pre-contrast T1 measurement (PreT1), 2) post-contrast T1 measurement (PostT1), 3) partition coefficient (PC), and 4) volume of distribution (VD). We sought to evaluate the accuracy of LGE and various T1 mapping techniques for the assessment of myocardial fibrosis in patients with SSc.CMR was performed in 13 SSc patients (5 diffuse and 8 limited cutaneous) and 13 age-matched controls. Cine, pre- and post-contrast T1 mapping, and late gadolinium enhanced (LGE) imaging was performed. Calculation of PC and VD were: PC = ΔR1myocardium/ΔR1bloodpool. VD = [ΔR1myocardium/ΔR1bloodpool × p × (1 - hematocrit)] - Vp, where R1 = 1/ T1, ΔR1 is post-contrast - pre-contrast R1, p is myocardial specific density (1.05), and Vp is myocardial plasma volume fraction (0.045). The modified Rodnan skin score (mRSS), a measure of SSc disease activity, was quantified in all SSc patients by clinicians blinded to all CMR data.There was no visible LGE in 10/13 SSc and 13/13 controls. VD was significantly higher in SSc than controls , even when patients with visible LGE were excluded . PreT1, PC, and VD all correlated significantly with log mRSS in SSc patients, the correlation for PostT1 was not significant (Figure This is the first study to compare various T1 mapping techniques for the assessment of diffuse interstitial myocardial fibrosis in patients with SSc. PreT1 provides a surprisingly good assessment of DF in SSc, and may be useful in patients with impaired renal function. Calculation of VD - which requires measurement of hematocrit, PreT1, and PostT1 - is more time consuming but provides the most accurate assessment of DF in SSc. Calculation of PC and PostT1 - which allow one to eliminate hematocrit or hematocrit and PreT1, respectively - provide simpler but less accurate measures of DF in SSc.None.


Pulmonary hypertension (PH) is the end result of a variety of diverse pathologic processes. The chronic elevation in pulmonary artery pressure often leads to right ventricular pressure overload and subsequent right ventricular failure. In patients with left-sided cardiac disease, PH is quite common and associated with increased morbidity and mortality. This article will review the literature as it pertains to the epidemiology, pathogenesis, and diagnosis of PH related to aortic valve disease, mitral valve disease, left ventricular systolic and diastolic dysfunction, and pulmonary veno-occlusive disease. Moreover, therapeutic strategies, which focus on treating the underlying cardiac pathology will be discussed. Pulmonary hypertension (PH) occurs with an overall prevalence estimated at 15 per one million individuals [The most up-to-date classification system categorizing patients with PH into groups based on the underlying disease process leading to PH was published in the European Society of Cardiology Guidelines in 2009  [2]. Of Consensus guidelines define pulmonary arterial hypertension (PAH) as a mean pulmonary artery (PA) pressure greater than 25 mm Hg in the setting of a pulmonary capillary wedge pressure (PCWP), left atrial (LA) pressure, or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg [Transthoracic echocardiography is recommended as a screening test in the evaluation of suspected PAH, and this will provide essential information regarding concomitant left-sided valvular or ventricular dysfunction . In someCareful analysis of the invasive hemodynamic data is critical to making a correct diagnosis and recommending the appropriate therapeutic options. As will be discussed in detail in following sections, the vast majority of patients with PH in the setting of an elevated PCWP should not be treated with PAH vasodilator therapies. In order to ensure the accuracy of the PCWP data, close attention should be given to the fidelity of the a-, c-, and v-wave morphologies on the PCWP hemodynamic tracing. Furthermore, the PCWP should be measured at end-expiration . If there is any question about the PCWP validity, then some advocate a PCWP wedge saturation (it should be similar to pulmonary venous saturation if done properly) and/or direct measurement of the LVEDP for confirmation.Vasodilator challenge is an integral element in the assessment of suspected PAH and should be conducted for patients with a mean PA pressure ≥25 mm Hg and a PCWP ≤15 mm Hg. For patients with a PCWP >15 mm Hg, vasodilator testing should generally not be performed, or if it is performed, then it should be done with close hemodynamic monitoring by experienced clinicians with expertise in the evaluation of PAH due to the risk for development of acute pulmonary edema and sudden respiratory compromise. Approximately 10% of patients with PAH have a positive response to vasodilator challenge, defined as a decrease in mean PA pressure by >10 mm Hg to an absolute mean <40 mm Hg without a decrease in systemic blood pressure or cardiac output , 8. OthePulmonary venoocclusive disease (PVOD) is a rare entity characterized by obliterative fibrosis of small pulmonary veins . It is eGiven the relative infrequency of PVOD in the population, it is a challenging disease to characterize and study. Small studies have suggested a statistical association between PVOD among male gender and a history of smoking when compared to a population of idiopathic PAH patients . The cliDespite advances in the management of patients with idiopathic PAH using vasodilator therapy, clinical improvement has not been seen in PVOD-related PAH, and many patients actually clinically deteriorate with the onset of severe pulmonary edema after initiation of such agents due to the obstruction in pulmonary venous outflow. Several recent reports have suggested that epoprostenol may play a role in bridging patients with PVOD to lung transplantation . HoweverFinally, other obstructive lesions to pulmonary venous drainage have been observed clinically and reported in the literature infrequently. Pulmonary vein stenosis is one of these lesions and can be either congenital or acquired. Acquired pulmonary vein stenosis has been noted after electrophysiologic ablation procedures and in patients with sclerosing mediastinitis. Also, cor triatriatum sinister and atrial myxoma have the potential to impair pulmonary venous drainage into the left atrium with the subsequent development of PH.Elevation of PA pressures is commonly observed in patients with both MS and MR. The presence or absence of PH with mitral valve disease is a key element in the decision-making algorithm for percutaneous or surgical intervention on the mitral valve in the most recent American College of Cardiology/American Heart Association Valvular Heart Disease guidelines . The mechanism by which PH develops in patients with mitral valve disease is driven by an elevation of LA pressure, which in turn, leads to pulmonary venous hypertension, and subsequently, pulmonary arterial hypertension to deliver deoxygenated blood across the lungs from the right heart to the left heart. Left atrial compliance is often reduced resulting in an increased “v” wave in mitral valve disease. In patients with MS, the elevation in LA pressure also results from the abnormal diastolic pressure gradient across the dysfunctional mitral valve, while in patients with chronic MR, a further increase in LA pressure results from the regurgitant systolic jet and the rise in LV end-diastolic pressure.With MS, there are two well-characterized associated hemodynamic states. Initially, with progression of MS, the mitral valve area (MVA) and cardiac output decrease with a concomitant rise in the LA pressure . Later iMitral stenosis, when moderate to severe, is associated with a variable degree of PH in the majority of patients. The pathophysiology of PH in MS involves structural alteration of the pulmonary vascular bed mediated by the potent vasoconstrictor endothelin-1 (ET-1) . Levels The American College of Cardiology (ACC)/American Heart Association (AHA) Valvular Heart Disease guidelines recommend intervention to relieve MS with percutaneous balloon mitral valvuloplasty (PBMV) if the valve morphology is favorable with a Wilkins score less than 8 and less than moderate MR, or surgical MVR, when PH is present . More sp5 and subsequently exhibited additional reduction to 280 dynes × sec/cm5 at 7-month follow-up catheterization [A large body of outcome data exists for PBMV in mitral stenosis. Early work in the PBMV era showed that PA pressures fell immediately after PBMV, in concert with the reduction in mitral valve gradient . In the rization , 16. Furrization , 18. ThuSurgical correction with mitral valve repair or replacement is the treatment of choice for chronic severe mitral regurgitation. For patients with increased predicted perioperative morbidity and mortality, percutaneous intervention with the MitraClip device may be considered. The most recent ACC/AHA management guidelines endorse mitral valve intervention if symptoms are present or in asymptomatic patients with a left ventricular ejection fraction (LVEF) less than 60%, a left ventricular end-systolic diameter greater than 4 cm, a resting PA systolic pressure greater than 50 mm Hg, or a PA systolic pressure greater than 60 mm Hg with exercise . 2 [2 from baseline values to the end of the study period [Most of the clinical studies evaluating surgery for patients with mitral valve disease and PH included both MS and MR. Thus, the surgical outcomes for MS and MR will be reviewed together. Without relief of mitral valve obstruction, observational data from several decades ago demonstrated that mean survival was 2.4 years when severe PH was present with MS . Several2 . There w2 . The meay period . Anothery period . This woy period . All paty period . Approximately 25 years after this original work, invasive hemodynamic evaluation from 22 patients with rheumatic mitral valve disease at preoperative baseline, and at 6 and 12 months following postoperative baseline was published . This st Finally, the acute hemodynamic response to bileaflet mechanical MVR was reported in 60 patients with PH from the modern era . This puPatients with PH secondary to mitral valve disease have been excluded from the clinical trials evaluating the current United States Food and Drug Administration (FDA)-approved PAH pharmacologic vasodilator therapies. Case reports describing the safety and efficacy of various vasodilator agents during the immediate postoperative period in patients undergoing mitral valve surgery with preoperative PH have been published. The agents utilized include inhaled prostacyclin, inhaled nitric oxide, intravenous nitroprusside, and inhaled iloprost, and the reports focused on acute hemodynamic changes with the respective agents –29. The In addition, there are isolated case reports detailing the use of PAH pharmacotherapies as chronic therapy in patients with mitral valve disease and PH. The use of epoprostenol in this manner was reported in a patient with residual severe PH after MVR. There was an improvement in functional status and hemodynamics with a decrease in mean PA pressure and an increase in cardiac output . LikewisValvular AS is one of the most frequently encountered pathologies in the practice of adult cardiovascular medicine. However, the association of PH with severe AS is often underappreciated and varies with the threshold used for the detection of the presence of PH. Aortic stenosis results in PH by creating LV diastolic dysfunction and subsequent pulmonary venous hypertension due to associated LV hypertrophy and reduced LV diastolic function. One of the original systematic characterizations of PH in patients with severe AS reported a prevalence for PH of 50% using the threshold of a PA systolic pressure of >30 mm Hg . In thisSeveral echocardiographic studies have examined the relationship between severe AS and PH. In a small study involving 50 patients with severe AS and PH, multivariate analysis revealed that diastolic function as assessed by E/e' was the only independent predictor of PH . However2 [Surgical aortic valve replacement (AVR) is the recommended therapeutic intervention for patients with symptomatic, severe AS with a mean gradient greater than 40 mm Hg or an aortic valve area less than 1.0 cm2 . Likewis2 . However In one study, the characteristics of 47 patients with severe AS and severe PH during the time period of 1987 to 1999 were analyzed, and the outcome demonstrated that perioperative mortality was 16% . For theBased on analysis of nonrandomized, observational data, AVR in patients with severe PH and AS is associated with increased perioperative mortality compared to patients without PH. However, AVR is also associated with improved long-term survival and should be considered in selected patients at experienced, high-volume surgical centers. Based on the dramatic results of initial clinical trial data, transcatheter aortic valve replacement will also likely be an option in the future for patients with severe AS and PH who are at high risk for surgical AVR due to other comorbid conditions. At the present time, even isolated case reports on the use of pulmonary vasodilators in patients with severe PH and AS are lacking from the literature and the use of such agents cannot be recommended.Elevation of pulmonary artery pressures secondary to isolated aortic valve regurgitation (AR) is less common than with other valve lesions but does occur. Prior studies have reported a prevalence of PH in 10–20% of patients with severe AR . The patIn chronic AR, surgery to replace the aortic valve is indicated when there are symptoms present with severe AR or with asymptomatic severe AR when the LVEF is less than 50% or there is dilation of the LV . RetrospAlthough limited by potential selection bias, this work suggests that AVR can be performed with acceptable perioperative risk in patients with severe PH due to AR. In addition, it also highlights the recurrent theme that valve surgery is often associated with a significant improvement in PA pressures and improved survival based on observational datasets.Heart failure with preserved systolic function accounts for over half of hospitalizations for congestive heart failure. This category represents a varied group of disease states including systemic hypertension, hypertrophic cardiomyopathy, infiltrative cardiomyopathies, Fabry's disease, and obstructive sleep apnea. Some of these patients will develop PH as a response to the abnormal diastolic filling of the LV. Likewise, there is a growing population of elderly patients with dyspnea who have PH in which HF with preserved LVEF appears to be the most common cause . The comThe epidemiology and association of PH in patients with normal LV function and diastolic dysfunction have been well recognized over the last decade. A recent population-based study of 244 patients with HF and preserved LVEF observed PH in 83% of patients as defined by an echocardiographic Doppler estimation of PA systolic pressure greater than 35 mm Hg [For the diagnosis of PH related to impaired diastolic filling, other potential causes of PH must be excluded. Right heart catheterization is obligatory and will usually reveal an elevated PCWP and LVEDP, mean PA pressure, and in some patients an elevated PVR with an exaggerated TPG gradient. Although not part of the diagnostic criteria in the PH guidelines, invasive hemodynamic evaluation with supine bicycle or arm weight exercises may occasionally be useful to better understand the symptomatic limitation of individual patients with suspected PH due to diastolic dysfunction .At the present time, there are no guideline recommendations or clinical trial data regarding the management of PH in diastolic HF . GeneralPulmonary hypertension is commonly found in patients with left ventricular systolic dysfunction. It has been reported that two-thirds to three-fourths of patients with systolic heart failure (HF) due to ischemic or nonischemic cardiomyopathy have associated PH . HoweverGreater understanding of the physiological mechanisms of PH in HF with systolic dysfunction has evolved over the last two decades. The circulating peptide ET-1 is a potent vasoconstrictor and seems to play a role in the development of PH with MR. Elevated levels of circulating ET-1 in HF have been linked to higher PA pressures and PVR . MoreoveSymptoms such as shortness of breath at rest and with exertion are a major manifestation of systolic HF, which negatively impact activity level and quality of life. In patients with a reduced LVEF, the concomitant presence of PH correlates with more advanced symptom status and greater functional impairment as reflected by a statistically higher NYHA class than a similar cohort with LV systolic dysfunction without PH . This efWhen PH is present with systolic HF, it is also associated with increased risk of death , 52. OneSelected patients with advanced HF symptoms and severe LV systolic dysfunction are often considered for orthotopic heart transplantation. Multiple studies have examined the impact of PH on outcomes in patients undergoing transplant. The synthesis of the various studies shows that when a PVR greater than 2.5 Wood units and a TPG gradient greater than 15 mm Hg is present, there is an increase in mortality at 3 month and 1 year posttransplant . MortaliThere appears to be an expanding role for the LVAD as a bridge to heart transplant in the management of patients with severe left ventricular systolic HF and PH. Several studies in patients with systolic HF and severe PH have demonstrated that an elevated PVR despite pharmacologic therapy is often reduced to <2.5 Wood units over a 6 month time period following LVAD placement –62. RetrAlthough there are no FDA-approved agents for the treatment of PH due to LV systolic dysfunction, the use of long-term pulmonary vasodilator therapy has been attempted to improve symptoms. Early work in this area with chronic epoprostenol administration in the Flolan International Randomized Survival trial (FIRST), however, observed an increased mortality in the cohort with LV systolic dysfunction; the trial was terminated early by the Data Safety Monitoring board . SubsequMilrinone, an inhibitor of type 3 phosphodiesterase, is an inotrope and systemic vasodilator used in the management of acute decompensated HF from LV systolic dysfunction. It also has hemodynamic actions on the pulmonary vasculature by decreasing PVR and augmenting RV function . In clin Finally, the type 5 phosphodiesterase inhibitor, sildenafil, which is approved for chronic therapy of idiopathic PAH, has been evaluated in PH with systolic HF. During a 6 month randomized trial of sildenafil or placebo in 46 patients with mild PH and systolic HF, there was statistically significant reduction in PA pressures and an increase in peak oxygen consumption during CPX testing, without adverse side effects reported . SimilarIn conclusion, PH frequently develops in response to left-sided cardiac disease due to elevated pulmonary venous pressure and is associated with a series of lesions that range from diseases of the pulmonary veins, mechanical obstruction in the LA or at the mitral valve, or to elevation in the left atrial and pulmonary venous pressure due to mitral regurgitation, abnormal LA compliance, or to LV diastolic dysfunction. In some patients, secondary pulmonary hypertension appears to occur in addition. Pulmonary hypertension is associated with increased morbidity and mortality. In the setting of PH-related to left-sided obstructive or regurgitant valve disease, the PA pressures commonly decrease significantly or return to normal after valve replacement, repair, or mitral valvuloplasty; unfortunately this does not occur in all.  For patients with left ventricular systolic/diastolic dysfunction, the prognosis and options for treatment of associated pulmonary hypertension independent of therapy for the left heart disease are less favorable. Although not included in the vast majority of PAH vasodilator therapy clinical trials, vasodilator therapy may be of clinical benefit in a few carefully selected patients with left-sided cardiac disease in whom PH does not improve after addressing the underlying cardiac pathology.


Severe right ventricular dysfunction (RVD) is an important prognostic parameter in dilated cardiomyopathy (DCM). The relationship between myocardial fibrosis of the left ventricle (LV) and particularly the septum and right ventricular (RV) function remains poorly understood. We sought to investigate this relationship in a large cohort of DCM patients using cardiovascular magnetic resonance (CMR).We studied 257 patients  with known DCM using a clinical 1.5 T CMR scanner (Philips Achieva). Short axis slices covering entirely both ventricles were acquired using standard SSFP-sequences for measurement of LV and RV volumes and ejection fraction (EF). Focal myocardial fibrosis was assessed in late gadolinium enhancement (LGE) CMR images acquired 10 minutes after i.v. injection of 0.2mmol/kg Gd-DTPA (Magnevist). SSFP and LGE CMR images were assessed by different observers who were blinded to measurement results and clinical data. Severe RVD was defined as RVEF<35%. In a subgroup of patients (n=96) invasive measurement of pulmonary artery pressure was performed.Mean LVEF was 35±14% while mean RVEF was 42±13%. Focal myocardial fibrosis was present in 92 (36%) patients and was located a) intra-murally within the inter-ventricular septum in 29 patients (LGE -septum) or b) sub-epicardially/diffuse in 63 patients (any-LGE). None of the patients had sub-endocardial LGE. LGE-septum patients exhibited a significantly higher RVEF , a higher RV EDV index  and a higher RV ESV index  compared to the patient group with `any-LGE`. LVEF was not significantly different  between the two LGE-groups. Fifty-five (21%) patients had severe RVD (<35%RVEF) with a mean RVEF of 24±8%. The presence of myocardial fibrosis  was not significantly associated with severe RVD (p= 0.23). Also, there was no age and gender dependency in RVD. Invasively, RVD patients had significantly higher pulmonary artery pressure . RV EDV index correlated significantly with pulmonary artery pressure .The presence of LGE indicating focal fibrosis is not related to severe RV dysfunction in DCM. Interestingly, patients with ventricular septal fibrosis, i.e. mid wall sign, exhibited superior RV function. This may be explained by the pronounced mechanical shear stress exerted by the well-functioning RV on the inter-ventricular septum, potentially inducing focal myocardial fibrosis in DCM patients.none


A two-stage explantation of a left ventricular assist device (LVAD) was performed on 47 year old afro-american gentlemen with non-ischemic dilated cardiomyopathy (DCM) who was successfully bridged to recovery. After he suffered a stroke caused by a VAD thrombosis with embolisation, the VAD outflow graft was first ligated using minimally-invasive approach. Two months later, the device was explanted and a manufactured titanium plug was placed into the sewing ring. This stepwise procedure might be beneficial in cases of high thromboembolic risk and in patients who suffered a thromboembolic event previously. Ventricular assist devices (VADs) provide an established mechanical support of patients with end-stage heart failure as bridge to transplantation, bridge to recovery and chronic support .However, successful LVAD explantation can only be performed in a restricted number of patients who meet the criteria of myocardial recovery ,3. In thThe new miniaturized centrifugal HVAD® Pump  is a novel third generation VAD. One of the most significant design advantages of the HeartWare HVAD Pump is its size, intrapericardial placement and versatility in terms of implant options . Due to Full sternotomy LVAD explantation is shown to be feasible; however it might be associated with increased risk of intraoperative bleeding, need for blood transfusions and postoperative ventricular dysfunction. This problem might be partially resolved by LVAD explantation via minimally invasive lateral thoracotomy . However2 max) on support was almost constant at 2,700 rpm and 1,800 rpm. A transthoracic echocardiogram (TTE) confirmed no serious heart dilatation after 15 min of exercise. Due to these evident signs of myocardial recovery the patient was admitted for an elective LVAD removal.A 47-years-old afro-american gentleman diagnosed with non-ischemic dilated cardiomyopathy (DCM) underwent a continuous-flow LVAD (HeartWare) implantation as a bridge to transplantation. Postoperatively, the device flow was 6.6 L/min, left ventricular ejection fraction (EF) was 16%, and the left ventricular systolic (LVESD) and diastolic (LVEDD) diameters were 63 and 71 mm, respectively. After an uncomplicated postoperative course, the patient was discharged home. Six month later, his cardiac parameters improved significantly . The exercise test according to Modified Bruce Protocol [Unfortunately, he suffered a right fronto-parietal lobe infarct a night before the elective operation. The main areas of neurological impairment were left arm weakness, language and attention. Suggesting a thrombotic formation in the device and a displaced thrombus causing the stroke, three days after this event the LVAD was stopped; the outflow graft Figure  was ligaAfter two months, the LVAD pump was electively explanted through median sternotomy in off-pump technique. A manufactured titanium plug was placed into the inflow sewing ring which was left in place. Postoperative examination of the pump confirmed a dense thrombus formation with a soft red thrombus cast around the impeller of the device. With a quick postoperative recovery, the patient was discharged home with stable condition, satisfactory cardiac parameters and improving neurological status. From the myocardial recovery point of view, there have been no acute heart failure symptoms, no orthopnea and no peripheral oedema over 6 months follow-up.The two-stage LVAD explantation in patients with myocardial recovery and high risk of thromboembolic events offers several advantages compared to the conventional approach. The ligature of the VAD outflow graft through a small intercostal incision might prevent thrombotic flush from the VAD which can occur during extensive dissections during conventional LVAD explantation. Also, patients who already suffered an embolic stroke might benefit from additional time for recovery from previous stroke before LVAD is explanted. Furthermore, such a stepwise approach might reduce intra- and postoperative complications, such as right ventricular dysfunction and bleeding with the need for massive transfusions.In our case, the sewing ring of the LVAD was not removed but was closed using a manufactured titanium plug. As previously described, this approach may reduce the risk of perioperative bleeding and infections . Also, tPrevious research describes thrombolysis also as a suitable treatment of VAD thrombosis. However, performed in emergency and in the setting of thrombolysis and anticoagulation introduced for VAD thrombosis, it may lead to severe bleeding complications. Furthermore, in our particular case, the VAD explantation was the best option due to recovery of myocardial function.The risk of perioperative complications might be minimized even more if the VAD explantation is also performed without cardiopulmonary bypass . This teThe two-stage VAD explantation is a well reasonable option in cases of high thromboembolic risk and in patients who suffered a thromboembolic event previously.A written informed consent was obtained from the patient’s next of kin for publication of this case report and 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.AS wrote the manuscript; BH, PNM and AFP co-wrote the manuscript and managed figures; DG and JF were involved in the concept, TW, MA, TW, and ARS made critical revision of the manuscript, TB approved the manuscript. All authors read and approved the final manuscript.