Tissue Doppler imaging (TDI) is a noninvasive echocardiographic method for the diagnosis of diastolic dysfunction in patients with varying degrees of aortic stenosis (AS). Little is known however, on the utility of TDI in the serial assessment of diastolic abnormalities in AS.The aim of the current proposal was to examine whether treatment with rosuvastatin was successful in improving diastolic abnormalities in patients enrolled in the Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin (ASTRONOMER) study.Conventional Doppler indices including peak early (E) and late (A) transmitral velocities, and E/A ratio were measured from spectral Doppler. Tissue Doppler measurements including early (E') and late (A') velocities of the lateral annulus were determined, and E/E' was calculated.The study population included 168 patients (56 ± 13 years), whose AS severity was categorized based on peak velocity at baseline . Baseline and follow-up hemodynamics, LV dimensions and diastolic functional parameters were evaluated in all three groups. There was increased diastolic dysfunction from baseline to follow-up in each of the placebo and rosuvastatin groups. In patients with increasing severity of AS in Groups I and II, the lateral E' was lower and the E/E' (as an estimate of increased left ventricular end-diastolic pressure) was higher at baseline (p < 0.05). However, treatment with rosuvastatin did not affect the progression of diastolic dysfunction from baseline to 3.5 year follow-up between patients in any of the three predefined groups.In patients with mild to moderate asymptomatic AS, rosuvastatin did not attenuate the progression of diastolic dysfunction. Aortic stenosis (AS) is the most common valvular heart disease in adult subjects in North America ,2. It caTissue Doppler imaging (TDI) is recognized as a noninvasive tool to determine abnormal LV relaxation, and has been shown to be effective in analyzing left ventricular diastolic function in relation to mitral annulus velocity -7. In paThe aim of the current study was to examine whether treatment with rosuvastatin was successful in improving diastolic abnormalities in patients with mild to moderate AS.Between 2002-2005, 272 patients from 23 Canadian centers with mild to moderate AS were recruited for the Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin study (ASTRONOMER), a multicenter randomized trial to evaluate the effects of rosuvastatin on the progression of AS . PatientFor the purpose of the current subanalysis of the ASTRONOMER study, only those individuals with complete and analyzable diastolic echocardiographic parameters at the culmination of the study were included. The final cohort included 168 patients in whom diastolic echocardiographic parameters were available both at baseline and at study end. The study protocol was approved by the institutional review boards at the various participating centers.Parasternal and apical views were obtained using standard echocardiographic systems and multifrequency transducers with tissue Doppler capability. Standard two-dimensional images, M-mode, spectral and color Doppler, and TDI were performed. LV interventricular septal thickness, posterior wall thickness, and LV ejection fraction were determined from two-dimensional images according to established criteria . LV massTransmitral LV filling velocities at the tips of the mitral valve leaflets were obtained from the apical four-chamber view using pulsed-wave Doppler echocardiography. The transmitral LV filling signal was traced manually, and the following variables were obtained: peak early (E) and late (A) transmitral velocities, E/A ratio, and E-wave deceleration time. Tissue Doppler-derived indices were recorded at the lateral mitral annulus. These indices included systolic velocities (S'), early diastolic velocities (E'), and late diastolic velocities (A'). Finally, the dimensionless index of E/E' was calculated.p value less than 0.05 was considered statistically significant. The Statistical Analysis System 8.01 , was used to perform the analysis.The data is summarized as mean ± standard deviation or number (%). Within each arm, placebo and rosuvastatin respectively, baseline and follow-up values were compared using two-sample t-test. To compare changes in the clinical and echocardiographic variables between the two arms (placebo vs. rosuvastatin), all follow-up values were averaged, subtracted from baseline measurements, and the changes were compared using a two-sample t-test or Wilcoxon rank test depending on the distribution of the change. A The overall study population included 168 patients [92 males (55%)] with a mean age of 56 ± 13 years, who fulfilled the echocardiographic criteria. The patients were divided into three predetermined categories of AS severity based on peak velocity at baseline . Baseline and follow-up hemodynamics, LV dimensions and diastolic functional parameters were independently evaluated in all three groups.Baseline and follow-up data comparing the placebo arm to the treatment arm for Group I (2.5-3.0 m/s) are shown in Table All 64 patients in group I had conventional and TDI diastolic parameters assessed at baseline and 3.5 year follow-up Table . There wIn Group II (3.1-3.5 m/s), the peak AS gradient increased from 41 ± 4 mm Hg to 62 ± 23 mm Hg in the placebo arm, and 42 ± 4 mm Hg to 59 ± 14 mm Hg in the rosuvastatin arm , as shown in Table In Group III (3.6-4.0 m/s), the peak AS gradient increased from 56 ± 4 mm Hg to 80 ± 19 mm Hg in the placebo arm, and 56 ± 4 mm Hg to 79 ± 16 mm Hg in the rosuvastatin arm . There was no difference in progression of AS from moderate to severe amongst both groups (p = 0.85), as shown in Table In this observational sub-study from the ASTRONOMER trial, we sought to determine whether statin therapy improved diastolic dysfunction in patients with mild to moderate AS after a median follow-up of 3.5 years. There was increased diastolic dysfunction from baseline to follow-up in each of the placebo and rosuvastatin arms. In patients with increasing severity of AS in groups I and II, the lateral E' decreased and the E/E' increased over time within each arm, despite no change in LV mass nor LVEF (p < 0.05). However, there was no difference in progression of diastolic dysfunction from baseline to follow-up between patients in all three predefined groups with AS who received placebo versus rosuvastatin. To the best of our knowledge, this is the first clinical investigation that specifically examined the effects of statins on the progression of diastolic dysfunction in patients with AS.From a pathophysiologic perspective, the obstruction imposed on the LV from the stenotic AV produces systolic wall stress, which in turn leads to concentric LVH -4. AlthoIndolfi et al. examined the effect of simvastatin on chronic pressure-overloaded left ventricles in Wistar rats [ERK2 phosphorylation, which prevented the development of LVH in this murine model of chronic pressure overload. Similarily, Luo et al. demonstrated that simvastatin reduced LVH due to inhibition of local cardiac angiotensin converting enzyme (ACE) activity [It has been suggested that statins may have beneficial effects on diastolic parameters, predominantly by attenuating the degree of LVH and cardiac fibrosis in murine models of hypertension ,17. Indotar rats . The adm2), measures of diastolic function were abnormal and related to increasing severity of AS [2 and a mean transaortic peak velocity of 3.2 ± 0.5 cm/s [Lancelotti et al. evaluated patients with severe AS , in whom an E/E' ratio >14 identified a subset of patients at greater risk of future events [Bruch et al. demonstrated an impairment in diastolic function using TDI in symptomatic patients with advanced aortic AS and LVH [2 and mean transaortic pressure gradient of 57 ± 17 mm Hg [Bruch et al. demonstrated that the E/E' ratio allows for a reliable and reproducible estimation of LV filling pressures in patients with advanced AS, as compared to age-matched controls [A number of clinical studies have evaluated diastolic dysfunction in patients with varying degrees of AS severity -12. We pty of AS . Specifity of AS . Diastolty of AS . The sev0.5 cm/s . The LV 0.5 cm/s . Lanceloe events . FinallyFukuta et al. suggested that statin therapy may lower mortality in patients with diastolic heart failure due to its pleotropic effects in hypertension and CAD [Despite the lack of clinical studies examining the effect of statins on preventing diastolic dysfunction in AS patients, a study by  and CAD . In this and CAD . Statin  and CAD . The finThe results of our study are unique in that it is the first to directly evaluate the effects of statins on preventing the progression of diastolic dysfunction in patients with AS. With increasing severity of AS, the degree of diastolic dysfunction, as reflected by a lower E' and higher E/E' ratio, is in agreement with previous studies described above -12. HoweThere were some important limitations in the current study. This was an observational sub-study of the ASTRONOMER trial. The original sample size was intended to answer the primary question of whether statins affect the progression of mild to moderate AS, rather than to evaluate the effects of statins on preventing diastolic dysfunction. Given the subgroup nature of these analyses, the results of the current study need to be interpreted cautiously. Although the ASTRONOMER study included 272 patients in total, the current subanalysis study included only 168 patients in whom diastolic echocardiographic parameters were available both at baseline and at study end. Furthermore, the sample size may have been too small to detect true changes even if they exist. Similar to other studies using TDI, the methodology is angle dependent and can be affected by cardiac translation, rotation or both. Additional measurements of diastolic function including medial TDI, LA volumes, strain, strain rate and Vp were not available. Finally, the baseline patients in the ASTRONOMER trial represent a fairly homogenous, Caucasian population, and therefore, it is difficult to extrapolate these results to other ethnic groups.In patients with mild to moderate AS, progression of diastolic abnormalities was observed over the 3.5 year follow-up. Rosuvastatin did not attenuate the progression of diastolic dysfunction in this patient population.The authors declare that they have no competing interests.DJ, KM, EK, MZ, JD, LT, JW and KC contributed to the writing of the manuscript. All authors read and approved the final manuscript.


Following the publication of our article  we have Figure 2. Example of a Change in Management. A 65 year-old man was referred for assessment of ventricular function and viability testing. CMR unexpectedly revealed a large apical thrombus, for which the patient was admitted to hospital for initiation of systemic anticoagulation.Figure 3. Example of a New Diagnosis. A 32 year-old woman with sickle cell anemia was referred for evaluation of iron overload by T2* imaging, which was normal. However, nearly transmural hyperenhancement (white arrows) was seen in the apical inferior wall on late enhancement imaging, indicative of previously unrecognized myocardial infarction.Please note, these changes do not affect the conclusions made in the original publication.


The effect of Transcatheter Aortic Valve Implantation (TAVI) on left ventricular (LV) geometry and function was compared to traditional aortic replacement (AVR) by major surgery.45 patients with aortic stenosis (AS) undergoing TAVI and 33 AVR were assessed by standard echo Doppler the day before and 2 months after the implantation. 2D echocardiograms were performed to measure left ventricular (LV) mass index (LVMi), relative wall thickness (RWT), ejection fraction (EF) and the ratio between transmitral E velocity and early diastolic velocity of mitral annulus (E/e’ ratio). Valvular-arterial impedance (Zva) was also calculated.At baseline, the 2 groups were comparable for blood pressure, heart rate, body mass index mean transvalvular gradient and aortic valve area. TAVI patients were older (p<0.0001) and had greater LVMi (p<0.005) than AVR group. After 2 months, both the procedures induced a significant reduction of transvalvular gradient and Zva but the decrease of LVMi and RWT was significant greater after TAVI (both p<0.0001). E/e’ ratio and EF were significantly improved after both the procedure but E/e’ reduction was greater after TAVI (p<0.0001). TAVI exhibited greater percent reduction in mean transvalvular gradient (p<0.05), Zva (p<0.02), LVMi (p<0.0001), RWT (p<0.0001) and E/e’ ratio (p<0.0001) than AVR patients. Reduction of E/e’ ratio was positively related with reduction of RWT  only in TAVI group, even after adjusting for age and percent reduction of Zva .TAVI induces a greater improvement of estimated LV filling pressure in comparison with major prosthetic surgery, due to more pronounced recovery of LV geometry, independent on age and changes of hemodynamic load. Aortic stenosis (AS) is the most common valvular heart disease in western countries . It induRecent observations have shown how TAVI could be followed by an immediate decrease in transaortic pressure gradient and a consequent reduction in LV afterload ,24. AlthThe study population included consecutive patients with symptomatic severe AS and high risk , who und2).Exclusion criteria included a bicuspid aortic valve disease (n=1) , previous acute myocardial infarction (n=3), significant coronary artery disease requiring revascularization (n=2), LV ejection fraction ≤ 30% (n=5), severe mitral or aortic valve regurgitation (n=3), atrial fibrillation (n=3), transient ischemic attack or stroke within the previous 6 months (n=1), and severe renal insufficiency  were collected and compared. Written informed consent was obtained from each patient. TAVI and AVR were performed according to the respective standardized procedures -33. Pati2.7 in women and ≥ 49 g/m2.7 in men. Two-dimensional LV end-diastolic and end-systolic volumes were measured by the modified Simpson method  and ejection fraction (EF) was calculated. Left atrial (LA) volume was assessed by the biplane area-length method from the apical approach, taking care to obtain multiple, dedicated views of the left atrium purposely oriented to maximize LA area and optimal definition of LA wall, according to a standardized method [2). Transmitral pulsed Doppler was recorded in the apical 4-chamber view. Early (E) and atrial (A) peak velocities (m/sec) and their ratio, and E velocity deceleration time were measured. By pulsed Tissue Doppler, early diastolic velocity (e’) was measured in apical 4-chamner view at the lateral mitral annulus. Attention was paid to the Doppler spectral gain settings and the velocity scale was kept at about 20 cm/s above and below the baseline. Minimal angulation (<20°) was maintained between the ultrasound beam and the plane of cardiac motion during the sampling of the lateral mitral annular site. The ratio of transmitral peak E velocity to peak e’ velocity was calculated as an estimate of LV filling pressure by using e’ velocity of lateral mitral annulus (E/e’ ratio). Valvular arterial impedance (Zva) was determined as an index of global LV load according to the formula = (ΔP + systolic BP)/SVI where ΔP = mean transvalvular systolic pressure gradient, BP = blood pressure and SVI = stroke volume index [Doppler echocardiographic exams were performed using a Vivid 7 ultrasound scanner  equipped with a 2.5 MHz phased-array transducer according to the standards of our laboratory ,36. All d method . LA volume index .Statistical analysis was performed by SPSS package, release 12 . Data are presented as mean value ± SD. Intergroup comparison at baseline was obtained by one-factor ANOVA. The comparison of data before and after surgery (time) and the impact of the procedure (treatment: TAVI vs. AVR) was be statistically assessed using a 2-way ANOVA for repeated measures. Least squares linear regression was used to evaluate univariate correlates of a given variable. The null hypothesis was rejected at p ≤ 0.05.The main clinical characteristics and main echo Doppler features of the 2 study groups at baseline are reported in Table Table Figure Per cent reduction of relative wall thickness was not significantly related to either transaortic mean gradient or Zva in both TAVI  and AVR group . Similarly, the per cent reduction of E/e’ ratio was not significantly related with transaortic mean gradient or Zva in both TAVI  and AVR group . In contrast, the percent reduction of relative wall thickness was positively related to the percent reduction of E/e’ ratio in the TAVI group  , found only in the TAVI group. This relation remained significant even after adjusting for age and percent reduction of Zva, an index of LV global load which accounts for the effects of both AS and systemic arterial compliance, is one of the main determinant of exercise capacity  and is pThe main limitation of the study is the short duration of the follow-up period of TAVI and traditional AVR patients. While the choice of 2-months period post-implantation can be judged to be useful in order to highlight the rapid effectiveness of TAVI in improving both LV structure and diastolic function, it should also important to verify whether this improvement could be sustained at longer follow-up. Further studies will be need to analyze this aspect.In conclusion, our study demonstrates that TAVI could induce a faster recovery of LV geometry than after traditional AVR and the shift from LV concentric remodeling/hypertrophy could be responsible in its turn of a better reduction of LV filling pressure, irrespective of changes in LV afterload.The authors declare that they have no competing interests.FMC, MG, GDS conceived of the study and participated in its design and coordination, performed the statistical analysis, drafted and revised the manuscript, ED participated in the study design and coordination and performed echo scans, PI, GT and MDN participated in the study design and coordination, FDS, CS and RE participated in the study design, performed and revised the statistical analysis and revised the manuscript. All authors read and approved the final manuscript.


This study was performed to investigate the relationship between elastic properties of aorta and left atrium volume index (LAVI) in hemodialyzed (HD) patients.2. Additionally several indices were calculated: left ventricle mass (LVM), left ventricle mass index (LVMI), midwall fractional shortening (mFS), endsystolic stress (ESS), mFS/ESS. Additionally the laboratory parameters including lipidogram, troponin T (cTnT), NT-proBNP and asymmetric dimethylarginine (ADMA) were measured.Study group was consisted of 73 patients  treated by hemodialysis. In all patients standard echocardiography was performed. Aortic stiffness index (ASI) was calculated using formula: ASI = log (SBP/DBP)/[(Aomax-Aomin)/Aomin]. LAVI was calculated according to the formula: LAVI = [π/6 x (LAmax x LAshort x LAlong)]/mThe ASI was strong and significantly correlated with left atrium volume (LAV) and LAVI . The ASI was independently and markedly associated with ADMA, cTnT, CRP, T-chol, and LDL-chol. The LAVI was independently and significantly correlated with NT-proBNP and cTnT.There is correlation between ASI and ADMA, marker of endothelium dysfunction. There is also association between LAVI and NT-proBNP, signs of elevated left atrium pressure. The strong correlation between ASI and LAVI, improved by associations of specific biochemical markers with these echocardiographic indices, suggests there is the link between elastic properties of aorta and left atrium pressure in hemodialysed patients mediated by endothelial dysfunction. Cardiovascular complications are the main cause of death in patients with end-stage renal disease (ESRD) on renal replacement therapy . Most ofLeft atrium (LA) enlargement is a hitherto overlooked component of the complex echocardiographic alterations that are observed in ESRD. In individuals with ESRD, left atrial volume (LAV) is independently associated with angiographically significant coronary artery disease, history of stroke, carotid intima-media thickness and signs of inflammation such as high concentration of hs-CRP . Left atBecause the LA is exposed to left ventricle filling pressures through the open mitral orifice during diastole, its size is influenced by the same factors that determine diastolic filling pressure. The diastolic dysfunction of the left ventricle is a common finding among patients with ESRD. One of the most important factors influencing left ventricle function independent of blood pressure is aortic stiffness .Atherosclerosis was regarded as a combination of two major separate diseases: atherosis and sclerosis. Sclerosis component depends on deterioration of aortic elastic properties and is called aortic stiffness. The stiffness of the aorta influences aortic conduit function causes pressure elevation and abnormal pressure pattern that increases the afterload of the left ventricle. In that way may induce left ventricle hypertrophy and alter on left ventricle diastolic and systolic function. It is well known that aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in different group of patients  includinEndothelial dysfunction is a crucial precursor of the development of cardiovascular disease. The endothelium maintains the balance between vasoconstriction and vasodilatation. The role of the endothelium in controlling the vascular tone, especially vasodilatation, has been shown via the endothelial-derived nitric oxide (NO) . DecreasThis study was performed to investigate the relationship between elastic properties of aorta and LAVI in hemodialised (HD) patients. Moreover the relationship between these functional and morphological parameters and selected biochemical markers was assessed.. During hemodialysis, no medication was applied except heparin. All patients were hemodialysed for >6 months and were clinically stable. Out of 73 HD patients, 46  were taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, 41  beta-blockers, 44  calcium blockers and 24  statins.Study group was consisted of 73 patients  treated by hemodialysis for mean time of 78,71 months. Hemodialysis were performed three times a week using devices as: Fresenius 4008B/S  and Gambro AK95S . Bicarbonate dialysate containing (in millimoles per litre) 32 bicarbonate, 136–138 sodium, 2.5–4.0 potassium, 1.0 magnesium and 1.25 or 1.5 calcium was used in all HD patients. The mean time of hemodialysis session was 4.09 ± 0.11 h. The diffusive technique was applied in all casesThe causes of ESRD in this group were as follow: glomerulonephritis – 32, diabetes mellitus – 11, chronic tubulo-interstitial nephritis – 3, obstructive nephropathy – 5, hypertonic nephropathy – 3, polycystic kidney disease – 4 and unknown/uncertain – 15.The control group comprised of 57 volunteers (27 women and 30 men) in age of 51,9 ± 7,1 years of comparable to study group clinical characterization, except that they didn’t suffer from ESRD. They have had no abnormalities detected by physical examination, ECG, chest X-ray and laboratory analysis.In all patient and control subjects standard transthoracic echocardiographic examination was performed using 2,5-3,5 MHz transducer  by the cardiologist, who was blinded to the clinical data of the study subjects. All echocardiographic measurements were done according to the guidelines of the American Society of Echocardiography . To excl2) and left atrium circumference (LAC[cm]). Consequently several standard indices were calculated according to American Society of Echocardiography recommendations ), fractional shortening of left ventricle (FS [%]). Using previously measured parameters the most important for present study indices were calculated according to formulas:The following a two-dimensionally guided M-mode echocardiographic parameters were recorded: interventricular endsystolic septum diameter (IVSSd [cm]), interventricular septum enddiastolic diameter (IVSDd [cm]), posterior wall systolic diameter (PWSd [cm]), posterior wall diastolic diameter (PWDd [cm]), left ventricle enddiastolic diameter (LVEDd [cm]), left ventricle endsystolic diameter (LVESd [cm]), left atrium maximal diameter (LAmax [cm]), aortic maximal diameter (Aomax [cm]), aortic minimal diameter (Aomin [cm]). The dimensions of the aorta were recorded in M-mode 3 cm above the aortic valve from a parasternal long axis view. The Aomax (systolic diameter) was measured at the time of aortic valve maximal opening. The Aomin (diastolic diameter) was recorded at the peak of the QRS complex. Inner aortic diameters were measured with a caliper in systole and diastole as the distance between the trailing edge of the anterior aortic wall and the leading edge of the posterior aortic wall . In 4-CHndations  such as:3]-13,6 g● Left ventricle mass (LVM [g]): LVM = 1,04x[(IVSDd + PWDd + LVEDd)2]): LVMI = LVM/BSA● Left ventricle mass index (LVMI [g/m3dyn/cm2]): ESS = 0,334xSBPxLVESd/PWSdx(1 + PWSd/LVESd),● Endsystolic stress : mFS=[(LVEDd + PWSd/2 + IVSSd/2)–(LVESd + Hs/2)/(LVEDd + PWSD/2 + IVSSd/2)]x100; where Hs = IVSSd + PWSd,● Ratio mFS/ESS [n],● Left atrium volume (LAV[ml]): LAV = LAVI= π/6x(LAmaxxLAshortxLAlong)  Figure ,2]): LAVI = LAV/m2● Left atrium volume index (LAVI [ml/m● Aortic stiffness index (ASI [n]): ASI = log [(SBP/DBP)/(Aomax-Aomin)]/Aomin  Figure .2 in men or > 110 g/m2 in women.Left ventricle hypertrophy was defined by a LVMI of > 134 g/mMoreover pulsed Doppler derived parameters were measured such as: maximal velocity of early diastolic transmitral flow (E [cm/s]), maximal velocity of late diastolic transmitral flow (A [cm/s]), isovolumetric relaxation time (IVRT [ms]), maximal systolic velocity in pulmonary veins (S [cm/s]), maximal diastolic velocity in pulmonary veins (D [cm/s]). Consequently ratios of E/A and S/D were calculated. Diastolic dysfunction was recognized accordingly to recommendation of Canadian Cardiovascular Society . PatientThe most important for this study echocardiographic indices were: LAVI and ASI. Patient from HD group were divided and compared using mean values of mentioned indices as cut-off values.2) = 0.0235 x height(cm)0.42246 x weight(kg)0.51456, creatinine [μmol/l], glomerular filtration rate (GFR) , urea [mg/l], uric acid [mg/dl], protein [g/l], albumin [g/l], high sensivity C-reactive protein (hs-CRP) [mg/ml], fibrinogen [g/l], total cholesterol (T-chol) [mg/dl], HDL-cholesterol (HDL-chol) [mg/dl], triglycerides (TGC) [mg/dl]. LDL-cholesterol (LDL-chol) [mg/dl] was calculated using the Friedewald equation: LDL-chol = T-chol – HDL-chol – (TGC/5). GFR was calculated from the modification of diet in renal disease (MDRD) formula: GFR = 186xserum creatinine-1.154 x age-0.203 x F, where F = 1 in men and F = 0,742 in women. Cardiac troponin T (cTnT)  in plasma was measured by the enzyme-linked immunosorbent assay - ELISA method  with the detection range between 0–640 fmol/ml. Asymmetric dimethylarginine (ADMA) [μmol/l] was measured by immunoenzymatic method – EIA  with the detection range between 0,05-3,0 μmol/l and reference range for healthy population of 0,4-0,75 μmol/l).The following standard parameters were measured by automated analyzer : hemoglobin [g/dl], sodium [mmol/l], potassium [mmol/l], calcium [mmol/l], phosphorus [mmol/l], Ca x P score [mgThe study protocol was approved by a university ethics review board. The investigation conforms with the principles outlined in the Declaration of Helsinki.Intraobserver variability for ASI and LAVI measurements were assessed. For intraobserver variability, a sample of 10 ASI and LAVI measurements was randomly selected and examined by the same observer in two different days after sessions of hemodialysis. Intraclass correlation coefficients for the same observer were calculated .Statistical analysis was carried out on an IBM PC using of a standard statistical package . Data were expressed as mean ± SD  and percentage . The statistical significance of the differences between HD patients and control group means were compared by unpaired Student’s t-test, the Mann–Whitney test, or chi-square test with Yates correction. Pearson’s test was used to calculate correlation coefficients. Multiple stepwise regression analysis was performed to estimate the potential influence of various laboratory, biochemical factors and both SBP and MBP on LAVI and ASI. The following independence parameters were entered into the model: hemoglobin, sodium, potassium, calcium, phosphorus, Ca x P score, creatinine, urea, total protein, albumin, hs-CRP, T-chol, LDL-chol, HDL-chol, TGC, cTnT, NT-proBNP, ADMA. Probability values of <0,05 were accepted as significant.Clinical characteristics and laboratory measurements of the study population and control group are listed in Table Baseline echocardiographic characteristic of the studied patients and controls are shown in Table The current study showed a significant correlation between the ASI and LAVI Figure . We have2, calculated for whole HD group, us cut-off value, in subgroups of LAVI < cut-off value were 38 patients  and in subgroup of LAVI > cut-off value were 35 persons . Similarly study group was divided into two subgroups due to mean calculated value ASI of 5,61 as a cut-off value. The first of these subgroups of ASI < cut-off value consisted of 37 patients with ASI 4,15 ± 1,74 and in second subgroup of ASI > cut-off value were 36 subjects with ASI 7,19 ± 1,62. The comparison of subgroups created by cut-off values of LAVI and ASI with regarding to selected hemodynamic and laboratory data are shown in Table After the division into subgroups using mean LAVI value of 36,29 ml/mThe ASI had been found independently and markedly associated with ADMA, cTnT, hs-CRP, T-chol, LDL-chol, but not with SBP and MBP in HD patients. Multiple stepwise regression analysis had been showed that the LAVI was independently associated with NT-proBNP and cTnT Table .Intraclass correlation for intraobserver variability was good for ASI measurements: 0,88; 0,77–0,95; 95% confidence interval. Intraclass correlations for intraobserver variability was also good for LAVI measurements: 0,85; 0,76–0,97; 95% confidence interval.Important observation of this study is that HD patients had greater LA dimension and therefore LAV and LAVI than control patients. These findings are important because it is well known that LAVI is an independent predictor of prognosis in HD patients providing information to traditional clinical and Doppler echocardiographic data . We have2 increase in indexed LA diameter was associated with a small but significant risk of increased cardiovascular mortality [In recent years, echocardiographic assessment of the LA and its relationship with cardiovascular risk have been revalued. LA size, particularly LAV has been recognized as a marker of diastolic dysfunction . Currentortality . Changesortality .In the present study NT-proBNP plasma level was significantly elevated in HD group. In literature there are conflicting data on the influence of glomerular filtration rate on BNP and NT-proBNP levels in ESRD. Tagore et al.  suggesteOur study has revealed for the first time highly significant correlation between LAVI and NT-proBNP among HD patients. Association between these two parameters was already described, but in other clinical settings. Kim et al.  documentThe higher values of LAVI with coexisting elevated plasma concentration of NT-proBNP may be a manifestation of so called cardio-renal syndrome . In thisWe evaluated that ASI was significantly higher in patients with ESRD than in subjects without renal dysfunction. It is well known that aortic elastic properties are affected by the risk factors for atherosclerosis. The coexistence of atherosclerosis and ESRD suggests there is the link between these two diseases . AtherosMultiple stepwise regression analysis has been shown that the ASI is independently associated with ADMA plasma concentration, troponin concentration, T-chol level, LDL-chol concentration and hs-CRP in HD patients. Our data demonstrate that HD patients have higher levels of ADMA. The ADMA is an endogenous competitive inhibitor of NO synthase. The ADMA competes with L-arginine. Therefore, NO levels decrease with increased ADMA levels. Recently, ADMA has been demonstrated to be a new and potentially independent marker of atherosclerosis and related cardiovascular disorders . EndotheAccelerated vascular damage and defective vascular repair have been proposed as a mechanism for premature atherosclerosis and aortic stiffness, common findings among HD patients. Impairment of NO biosynthesis  or NO bioactivity  causes endothelial vasodilatation dysfunction. Thereby, the correlations between ASI and oxygen-derived free radicals promoters such as T-chol, LDL-chol, hs-CRP, observed in the present study, were no surprised. The deleterious effects of T-chol, LDL-chol and hs-CRP in part a consequence of decreased availability of endothelium cells-derived NO, include smooth muscle proliferation, collagen synthesis, and deterioration of elastin which may impair arterial compliance . Taken tThe significant correlation was also detected between ASI and several parameters characterizing left ventricle function. This include correlation between ASI and parameters characterizing systolic function as ESS and mFS/ESS and also between ASI and diastolic parameters: E/A ratio, IVRT and S/D ratio. We can only speculate about the mechanism linking aortic stiffness with left ventricle dysfunction. Loss of aortic wall compliance causes pressure elevation and abnormal pressure pattern that increases the afterload of the left ventricle. The result is development of left ventricle hypertrophy also strongly associated with aortic stiffness in studied groups.The most important finding of echocardiographic aspect of the study was the significant correlation between ASI and LAVI in patients with ESRD. In our study, we found for the first time that HD patients with higher aortic stiffness have greater LAVI. There are several explanations for such association. Firstly, hypertension which is a common among patients with renal failure. It is well known that aortic stiffness is associated with LA size in hypertensive patients . AdditioIt is well known that increase of aortic stiffness predict the degree of left ventricular diastolic dysfunction . The maiThe results of this study suggest, that aortic elastic properties are impaired in hemodialyzed patients. The levels of ADMA, T-chol, LDL-chol and hs-CRP may be a biomarkers or mediators of aortic stiffness in this clinical setting. Both LAVI and NT-proBNP concentration, signs of elevated left atrium pressure are markedly increased in hemodialyzed patients. The strong correlation between aortic stiffness index and LAVI, improved by association of specific biochemical markers with these echocardiographic indices, suggests, that there is the link between elastic properties of aorta and left atrium pressure in hemodialysed patients mediated by endothelial dysfunction.The limitations of this study include its cross-sectional nature design with relatively small number of subjects. We do not investigate whether ASI still predict LAVI after adjustments for other significant co-variables including biochemical factors like NT-pro BNB, ADMA, cTnT. Finally, aortic stiffness may be influenced by clinical features that were not controlled in this study, eg. hypertension, diabetes, smoking etc. It remains to be determined whether these variables may alter presented association between aortic stiffness and LAVI in hemodialysed patients.HD: Hemodialysed patients; ESRD: End stage renal disease; IVSSd: Interventricular endsystolic septum diameter; IVSDd: Interventricular septum enddiastolic diameter; PWSd: Posterior wall systolic diameter; PWDd: Posterior wall diastolic diameter; LVEDd: Left ventricle enddiastolic diameter; LVESd: Left ventricle endsystolic diameter; LAmax: Left atrium maximal diameter; Aomax: Aortic maximal diameter; Aomin: Aortic minimal diameter; 4-CH: Four chamber; LAshort: Left atrium short diameter; LAlong: Left atrium longitudinal diameter; LAS: Left atrium surface; LAC: Left atrium circumference; SV: Left ventricle stroke volume; SI: Stroke index; CO: Cardiac output; CI: Cardiac index; EF: Ejection fraction; FS: Fractional shortening; LVM: Left ventricle mass; LVMI: Left ventricle mass index; ESS: Endsystolic stress; mFS: Midwall fractional shortening; LAV: Left atrium volume; LAVI: Left atrium volume index; ASI: Aortic stiffness index; E: Maximal velocity of early diastolic transmitral flow; A: Maximal velocity of late diastolic transmitral flow; IVRT: Isovolumetric relaxation time; S: Maximal systolic velocity in pulmonary veins; D: Maximal diastolic velocity in pulmonary veins; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MBP: Mean blood pressure; GFR: Glomerular filtration rate; hs-CRP: High sensivity C-reactive protein; T-chol: Total cholesterol; HDL-chol: HDL-cholesterol; TGC: Triglycerides; LDL-chol: LDL-cholesterol; MDRD: Modification of diet in renal disease (MDRD); cTnT: Cardiac troponin T; NT-proBNP: N-terminal fragment of brain natriuretic peptide; ADMA: Asymmetric dimethylarginine.The authors declare that they have no competing interests.TZ – carried out echocardiography, conceived of the study, and participated in its design, and coordination, and wrote the manuscript. AW - participated in its design, and coordination, and approved the manuscript. AK - conceived of the study, and participated in its design and coordination. AJ - analyzed and interpreted data conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/100/prepub


Cardiovascular Magnetic Resonance (CMR) is recognised as a valuable clinical tool which in a single scan setting can assess ventricular volumes and function, myocardial fibrosis, iron loading, flow quantification, tissue characterisation and myocardial perfusion imaging.The advent of CMR using extrinsic and intrinsic contrast-enhanced protocols for tissue characterisation have dramatically changed the non-invasive work-up of patients with suspected or known cardiomyopathy.Although the technique initially focused on the in vivo identification of myocardial necrosis through the late gadolinium enhancement (LGE) technique, recent work highlighted the ability of CMR to provide more detailed in vivo tissue characterisation to help establish a differential diagnosis of the underlying aetiology, to exclude an ischaemic substrate and to provide important prognostic markers.The potential application of CMR in the clinical approach of a patient with suspected non-ischaemic cardiomyopathy is discussed in this review. Cardiomyopathies encompass a broad spectrum of myocardial conditions which can affect the heart as a primary disease process or as part of a systemic disorder, evolving toward heart failure or cardiovascular death.Progress of modern molecular biology and its introduction into clinical cardiovascular medicine has considerably changed the approach to cardiomyopathies and has led to new classification schemes. .While cardiomyopathies were initially defined as disorders that were idiopathic, expert panels classify cardiomyopathies now into: primary, acquired and mixed . This reWhilst prevalence of dilated cardiomyopathy reaches 36 cases per 100 000 population, these figures as well as those reported for other cardiomyopathies, underestimate the frequency of the disorder as a number of patients are asymptomatic until reaching advanced stages of the disease. In addition, accurate diagnostic and prognostic phenotyping of cardiomyopathy remains a challenge owing to frequent overlapping features between individual cardiomyopathies.In the investigative workup for a suspected cardiomyopathy, typically a considerable number of tests are performed, ranging from the more routine and straightforward tests including ECG, echocardiogram, and exercise treadmill, to the more invasive including coronary angiography, electrophysiological studies, and endomyocardial biopsy. It is key to identify a potentially treatable substrate and then to risk stratify patients for treatment including consideration of an implantable defibrillator (ICD) or cardiac resynchronisation device.Advances in cardiovascular magnetic resonance (CMR) provide the potential to address all these important issues in a single scan setting complementing other non-invasive tools and genetic testing. The cost-effectiveness of non-stress CMR has been highlighted recently pointing out the ability of CMR to act as a cost-reducing gatekeeper to invasive coronary angiography in specific clinical settings .In a single 45–60 minute study, CMR can provide 3-dimensional data on cardiac anatomy, function, tissue characterisation, coronary and microvascular perfusion, valvular disease in any selected plane, regardless of patient’s habitus and without ionising radiation. The relative safety of gadolinium agents and tissue characterising sequences allows for repeated imaging, follow-up, family screening and serial risk stratification.In this review, non-ischaemic cardiomyopathies (NICMP) are approached from a clinical point of view outlining the diagnostic and prognostic role of CMR as an integral part of the clinical decision making algorithm.In the imaging workup of a suspected cardiomyopathy a wide range of sequences are acquired following dedicated protocols -8. FigurDark-blood imaging using mutislice single-shot spin-echo sequence  in trans-axial, coronal and sagittal planes allows a gross anatomical assessment in under 3 min. Alternatively 10–12 s breathhold images in each of the imaging planes using bright-blood imaging with steady-state free precession sequence (SSFP) can be performed.Dynamic long-axis and short-axis views of the heart are then acquired using breath-hold cine-SSFP imaging. Cine-CMR is accepted as the gold standard for accurate and reproducible quantification of left and right ventricular volumes, biventricular ejection fraction, and left ventricular (LV) mass obtained through manual planimetry or the use of semi-automated software . PresencSpecialised sequences allow characterisation of pathological tissue without the need for a contrast agent. The T2-weighted sequence, Short-Tau Inversion Recovery (STIR) is a powerful sequence for imaging oedema suppressing signal from flowing blood and from fat enhancing sensitivity to myocardial fluid content. Long T2 relaxation times of water-bound protons are used to generate a water-specific contrast resulting in high signal intensity of oedematous tissue ,15. STIRPitfalls include low signal-to-noise ratio, surface coil intensity variation, interfering bright signal from stagnant blood, motion artifacts and the subjective nature of interpretation ,22. SomeT1-weighted and turbo-spin echo sequences are useful to assess the pericardium and to look for fat infiltration.Myocardial T2*-mapping is a unique technique, validated against in-vivo histology, allowing direct identification and quantification of myocardial iron in vivo .Myocardial fibrosis or infiltration can be assessed following administration of gadolinium. Gadolinium is an extracellular agent accumulating in areas of interstitial expansion . Three phases can be assessed after gadolinium injection: the first pass (immediate imaging at rest or during stress), early enhancement (first 5 min) and late enhancement (5 to 20 min after injection). First pass can be used for perfusion imaging and is often given during vasodilator stress to detect myocardial ischaemia. Following intravenous injection of gadolinium (0.1-0.2 mmol/kg body weight), the contrast media is followed through the LV at rest and during pharmacologic stress to assess homogeneity of perfusion ,27. UltrEarly gadoliuium enhancement (EGE) imaging (1–3 min after injection) enables the detection of hypovascular regions such as dark, unenhanced intra-cardiac thrombi, and microvascular obstruction .Late gadolinium enhancement (LGE) imaging (5–20 min after injection) detects accumulation of contrast in areas of infarction or fibrosis due to slower contrast kinetics and greater volume of distribution in extracellular matrix.This is performed using inversion recovery Turbo-FLASH gradient echo or phase-sensitive inversion recovery (PSIR) in identical planes to the cine images searching for areas of fibrosis or infiltration. PSIR provides corrected images that are virtually insensitive for pre-pulse delay timing. It allows for a faster acquisition method without adjustment of inversion time and more consistent image quality to the expense of a lower spatial resolution ,30. ThisUsing inversion recovery sequences, focal fibrosis is imaged as a localised area of high signal intensity. The extent and pattern of LGE varies according to the underlying pathological process and contributes therefore to establish the correct diagnosis in NICMP Figure .Presence of fibrosis in NICMP is often only identified visually but its extent can be quantified as a percentage of total LV mass using dedicated software . All quaLGE imaging sequences delineate fibrosis by revealing a relative difference in T1-relaxation times between areas of scar (T1 shortened by accumulation of gadolinium) and normal myocardium . T1-mapping techniques work by measuring the absolute T1-relaxation time for all areas of myocardium on a pixel by pixel basis. As the shortening of T1 relaxation time is proportional to the local concentration of gadolinium, this can reveal subtle changes in T1 times due to expansion of the interstitial space with collagen and other fibrous tissue components. Early T1 mapping techniques were very time consuming. A Look-Locker sequence consisting of a gradient echo cine sequence with a nonslice selective inversion pulse after an R wave followed by a segmented gradient echo acquisition was developed ,39. Meane, (an index of fibrosis if the extracellular space is occupied by scar tissue) to be determined [The local concentration of gadolinium will be affected by several factors including the amount of scar, the rate at which gadolinium is cleared from the body but also by the amount of extracellular fluid available in the body for the contrast to distribute into . With thtermined ,44.While T1 mapping can accurately differentiate both interstitial and replacement fibrosis from normal myocardium, it cannot distinguish one type of fibrosis from another . To dateDespite a lower temporal resolution compared to echocardiography, assessment of valvular disease is achievable using CMR velocity mapping with reproducible results .CMR myocardial tagging quantifies myocardial deformation, contraction and relaxation in the radial, circumferential and longitudinal directions adding useful information particularly prior to resynchronisation therapy Figure . This teA feature tracking method has recently been made available for the post processing of routinely acquired SSFP cines using inhomogeneities of the tissue as identifiers, which are then identified by software algorithms for analysing regional function. Following manual contouring of the LV endocardial border of the first cine frame, the software automatically identifies and tracks endocardial and epicardial myocardial boundaries through the remaining phases of the cardiac cycle. Although the method has been compared to echocardiographic speckle tracking, it may be better described as ‘boundary’ tracking when applied to CMR SSFP acquisitions. Potentially derivable parameters include circumferential, longitudinal and radially directed velocity, displacement, strain and strain rate. However, some of these derived measures even more than others require cautious interpretation with respect to both spatial and temporal resolution of cine images, and the design of the software. Feature tracking based measures of global strain of short axis cine slices – essentially the relative change of length of the tracked endocardial boundary – have shown correlation with corresponding global strain measured by CMR myocardial tagging, with reduced values found in patients with Duchenne muscular dystrophy compared with volunteers and appeared as a promising technique to detect wall motion abnormalities during Dobutamine stress CMR -50. HoweAmongst limitations of CMR, metallic implants and intracardiac Devices  represent the only absolute contra-indication, but this will be overcome in the near future by new generation of CMR compatible pacing leads currently in clinical trials. Severe claustrophobia, clinical instability and the first trimester of pregnancy are among relative contra-indications. Even though gadolinium contrast agents are relatively safe, their use is restricted in chronic renal failure (GFR <30 ml/min) due to the small but tangible risk of nephrogenic systemic fibrosis (NSF) which is enhanced by concomitant heart failure . On the Cardiomyopathy is often suspected on the basis of symptoms, an associated abnormal ECG and echocardiographic findings. Following detection of ventricular hypertrophy, dilatation (right or left ventricles) or abnormal wall motion abnormalities after acute chest pain syndromes with unobstructed coronaries, characteristic imaging features on CMR greatly assist in reaching a diagnosis and providing prognostic information. The diagnostic and prognostic abilities of CMR in these various clinical conditions are reviewed. Detection of a hypertrophied LV highlights the differential diagnosis between a physiologic response to pressure overload  or pathological conditions such as hypertrophic cardiomyopathy (HCM), wall thickening due to myocardial infiltration (amyloidosis), or a glycogen storage disease (Fabry’s). CMR provides unique complementary information assisting the diagnostic process. The characteristic LGE findings distinguishing each entity are summarised in Table Although concentric LV hypertrophy (LVH) secondary to systemic hypertension (HTN), aortic stenosis (AS), or aortic coarctation is often suspected clinically and by echocardiography, CMR assists the diagnosis and provides important prognostic information. This is of particular interest in cases with discrepancies between clinical and imaging data such as marked hypertrophy unexplained by severity and duration of HTN where another underlying associated myocardial abnormality can be detected.In hypertensive hearts, CMR allows reproducible assessment of wall thickness and LV mass with greater accuracy compared to echocardiography which is particularly important for assessing small LV mass changes over time as a consequence of treatment but also of prognostic value as it represents an independent predictor of cardiac mortality ,54. Up taortic stenosis, LV mass predicts the development of heart failure independent of the degree of AS [Similarly to hypertensive hearts, in ee of AS . In addiee of AS ,60. The LGE is a frequent finding in adaptive LVH  probably related to myocardial injury secondary to mismatch between LVH and blood supply, and depends on the severity of LV remodeling . Amount However, diffuse fibrosis can be difficult to identify on standard LGE images. Myocardial signal with diffuse fibrosis will be nulled to highlight focal scar losing all information on background interstitial expansion. A growing body of publications have addressed this issue and several groups have extensively studied a way to detect interstitial fibrosis, validating T1 mapping to derive a fibrotic index -67 (see HCM represents the most common cause of sudden cardiac death (SCD) in the young, including trained athletes, and an important substrate for heart failure disability at any age. Various genetic mutations lead to a combination of myocyte hypertrophy, disarray and fibrosis.Although an abnormal ECG associated with marked asymmetrical septal hypertrophy and a dynamic LV outflow tract (LVOT) obstruction is almost diagnostic, individuals harbouring a genetic defect for HCM do not necessarily express clinical markers of their disease at all times during life. As a result, even normal or mildly increased LV wall thickness can be consistent with the presence of an HCM-causing mutant gene. Coexistence of HTN and HCM in a proportion of patients adds to the complexity. While HCM has been characterised by substantial LV wall thickening, Maron et al reported rather a spectrum of distribution and patterns of wall thickening .CMR offers the potential for high spatial resolution images with excellent border definition allowing accurate measurement of peak wall thickness and detection of localised hypertrophy especially in the apical variant of HCM and the basal anteroseptal wall, regions more difficult to image with echocardiography. LV apical aneurysms, conferring increased risk of SCD, ventricular arrhythmias, thrombo-embolic strokes and progressive heart failure, can be identified in 2% of HCM patients using CMR . In addiTypical patterns of LGE are patchy or confluent, generally confined to segments with greatest wall thickening and at the RV-LV insertion points  Figure C4A.Aside from its diagnostic value, LGE extent appears related to occurrence of ventricular arrhythmias at rest and during exercise and increased risk of SCD potentially contributing to risk assessment in borderline or controversial cases benefiting from a prophylactic ICD ,73. EvenCMR-detected myocardial fibrosis is associated with increased incidence of atrial fibrillation (AF) and heart failure, heralding advanced LV remodeling and systolic dysfunction ,75. InteDegree of LVOT obstruction and presence of systolic anterior motion of the mitral valve can be quantified using velocity flow mapping at rest and during stress and have been correlated with more extensive hypertrophy, worse heart failure symptoms and unfavourable outcome . CMR canWhilst no specific pattern of LGE has been identified in secondary LVH due to HTN or AS, focal non-subendocardial pattern has been described in the former and patchy sub-endocardial or mid-wall LGE in basal LV segments has been observed in the latter. This contrasts with the typical pattern of LGE seen in HCM patients affecting mainly insertion points and segments with maximal wall thickness Table .This common cause of infiltrative cardiomyopathy is classified as primary, secondary (reactive), hereditary, and age-related. Myocardial involvement represents an important prognostic marker of the disease influencing treatment options . DetectiTypical CMR findings include a small LV cavity size with homogeneously thickened walls affecting inconsistently also the right ventricle (RV). Bi-atrial enlargement, as a consequence of the restrictive cardiomyopathy, impaired long-axis function with preserved radial function until end-stages of the disease, thickened interatrial septum and valve leaflets, pleural and pericardial effusions resulting from interstitial amyloid fibrils deposition are among the classical features. Around 55% of patients with cardiac amyloidosis may present with asymmetrical septal hypertrophy mimicking HCM.Wassmuth et al, observed that accumulation of amyloid fibrils can change T2 relaxation times and demonstrated that myocardium appeared hypointense on T2-weighted images in cardiac amyloidosis. In addition, a lower T2 signal intensity ratio  was independently associated with shortened survival . FurtherWhile diffuse perfusion defects indicating microvascular dysfunction can be seen, the characteristic pattern of LGE and the peculiar kinetics of gadolinium are unique and discriminate this disease from other forms of hypertrophic cardiomyopathies. LGE reflects interstitial expansion by amyloid fibrils and appears as widespread, circumferential enhancement mostly of the sub-endocardium matching the distribution of amyloid protein on histology, giving rise to a characteristic ‘zebra’ pattern  Figure B4B. ThisFaster washout of gadolinium from blood into the total amyloid load leads to a technically challenging LGE acquisition with the inability to adequately null myocardial signal. High myocardial uptake and fast blood washout result in a dark blood pool due to similar myocardial and blood T1 values. To visualise myocardial and blood pool gadolinium kinetics before setting an inversion time when suspecting cardiac amyloidosis, an inversion time scout corresponding to an inversion-time mapping sequence with images generated at 30 ms inversion time increment, can be run early following contrast injection (less than 5 minutes). LGE has a reported sensitivity and specificity of 86% for the identification of cardiac involvement in patients with systemic amyloidosis, detecting early abnormalities in patients with normal LV wall thickness, and appeared strongly related to heart failure severity -82. AddiThis treatable cause of LV hypertrophy affects 1-2% of middle aged patients suspected of HCM . ConcentThe term DCM is applied in the presence of LV or biventricular dilatation and dysfunction following systematic exclusion of all obvious or detectable causes of cardiomyopathy. In up to 50% of cases the aetiology remains unknown, with 20-30% of familial cases attributed to known genetic abnormalities ,89. MyocDCM is the second most common cause of heart failure and the most frequent cause of heart transplantation. In addition to providing accurate and reproducible assessment of ventricular volumes and LVEF, the LGE technique detects a pattern of fibrosis in DCM which is typical mid-wall and seen in one third of cases. CMR by detecting the pattern of fibrosis contributes significantly to ruling out ischaemic aetiology and providing prognostic information.The specificity of the LGE pattern in ischaemic cardiomyopathy (ICM) has been underscored by several studies in which coronary angiography and CMR were performed in patients with systolic dysfunction of unknown aetiology .In a large study comparing patients with a diagnosis of DCM with unobstructed coronaries and patients with known coronary artery disease and a group of normal controls, three LGE patterns were reported . The iscPresence and transmurality of fibrosis in DCM has been linked to increased risk of SCD and ventricular arrhythmias independent of other markers of risk such as reduced LVEF ,92.Wu et al reported an eightfold increased risk of heart failure, ventricular arrhythmias and cardiac death in DCM patients with LGE referred for an ICD .Mechanisms contributing to fibrotic changes in DCM include inflammation, neurohumoral changes and microvascular ischaemia . LimitedWhilst the patterns of LGE observed in DCM patients are distinct from those seen in ICM, mid-wall but also epicardial, diffuse and focal patterns are seen ,93. It iAssomull et al, demonstrated recently that LGE was highly effective in detecting the underlying aetiology of newly diagnosed LV dysfunction and could be used as a safe and effective gatekeeper to coronary angiography . While pPilz et al, reported previously the role of Adenosine stress CMR as a gatekeeper to coronary angiography in a different patient population demonstrating the high accuracy of CMR in detecting significant coronary artery stenoses inducing 30% reduction in the rates of coronary angiography .A dilated RV of unexplained aetiology should raise the possibility of ARVC particularly if associated with aborted SCD from arrhythmias, often the first manifestation of the disease.This inheritable condition predominantly involving the RV with progressive loss of myocytes and fibrofatty tissue replacement can affect the LV in up to 75% of patients. In spite of recent advances in genotyping, clinical diagnosis remains challenging.While the classic phenotype describes progression of regional to global RV dysfunction, followed by LV involvement and biventricular failure, recognition of phenotypes with early and predominant LV involvement have raised questions regarding its differentiation from other myocardial disorders, such as DCM. Diagnosis relies largely on the ARVC Taskforce criteria, recently revised to include quantitative parameters for imaging studies, improving sensitivity of detection of gene-carriers with limited disease expression and those with left-sided disease features .2 for male and ≥100 ml/m2 for female or RVEF ≤40%; Minor criteria : Regional wall motion abnormality and RV end-diastolic volume ≥100- <110 ml/m2 for male and ≥90- < 100 ml/m2 for female or RVEF >40% - ≤45%) have been defined on the basis of comparison with normal patient data.These published cut-off values for RVEF and end-diastolic volumes  unexplained by significant coronary lesions . In a coKey features rely on the use of T2-weighted imaging increasing the sensitivity and specificity of detection of an ischaemic insult and on the typical pattern of LGE distinguishing an ICM from an NICMP and detection of myocarditis and Tako-tsubo  Figure B and 7.Myocarditis occurs with a wide spectrum of clinical manifestations ranging from flu-like symptoms to troponin positive CPS, severe heart failure and SCD. Endomyocardial biopsy recognised as the gold standard for the diagnosis remains limited by insensitivity and sampling bias.CMR can image several aspects of myocardial injury.In the acute stage of the disease, oedema following lymphocytic infiltration and myocytolysis appears as regions of high intensity on T2-weighted images. EGE matching areas of T2-hyperintensity may reflects tissue hyperemia and increased interstitial space .LGE identifies inflammation and fibrosis acutely and areas of irreversible necrosis in later stages, typically affecting the sub-epicardium sparing the sub-endocardium of the lateral wall Figure A. Mid-waAmong patients presenting with troponin positive CPS with unobstructed coronaries, CMR was able to identify a cause in 65% of patients with the commonest being myocarditis . In patiA large consensus group provided recommendations on the use of CMR in patients with suspected myocarditis suggesting the combination of 3 CMR criteria (‘Lake Louise criteria’) to increase the diagnostic accuracy . AuthorsAcute but rapidly reversible LV systolic dysfunction in absence of coronary artery disease, triggered by profound psychological stress characterises this stress-mediated myocardial stunning. Mid and apical LV segments akinesia with ballooning and compensatory hyperkinesia of basal segments producing a dynamic obstruction is a typical finding. RV is involved in 25% of patients.Focal and transient transmural hyperintensity on T2-weighted imaging reflecting oedema matching the distribution of wall motion abnormality seems to be a feature of Tako-tsubo cardiomyopathy related to the severity of LV systolic dysfunction . Lack ofRecently, Eitel et al analysed the CMR findings in Tako-tsubo cardiomyopathy in a large multicenter prospective cohort . These oThis multisystem granulomatous disease of unknown aetiology involves the myocardium in 20-30% of cases.Clinical myocardial involvement (5% of patients) ranges from asymptomatic conduction abnormalities to heart failure or fatal ventricular arrhythmias. An early diagnosis is crucial as current therapy may effectively prevent death from arrhythmias and cardiac failure. Endomyocardial biopsy and echocardiography proved insensitive diagnostic tools detecting mostly advanced stage of the disease.Although results of prospective data are awaited, CMR appears promising for the early diagnosis and for monitoring treatment response, providing novel risk stratification criteria for SCD and heart failure. T2-weighted and STIR imaging detect localised areas of myocardial inflammation. Cines identify areas of thinning and regional wall motion abnormalities and LGE detects focal scarring, typically patchy, mid-wall or sub-epicardial, frequently involving the anteroseptal and anterolateral walls  Figure .Patel et al described a large spectrum of LGE patterns. While the majority of affected myocardial segments had non-transmural involvement, explaining normal ventricular wall motion, there was a predilection for basal and mid-ventricular septum with up to 48% of regions displaying sub-endocardial LGE similar to coronary artery disease LGE. However, 86% of affected patients had also at least one region of LGE with a non-ischaemic type pattern. Sub-endocardial LGE of the RV side of the septum was a common finding and could be associated with LGE of the RV free wall .CMR appeared more sensitive for disease detection compared to Thallium SPECT and gallium SPECT . Recent This rare congenital disorder is characterised by a “spongy” appearance of the LV (and the RV in <50% of cases) resulting from an arrest in normal embryogenesis.LVNC may be associated with neuromuscular disorders, leading to heart failure, arrhythmias and thrombo-embolic manifestations. Although echocardiography is considered as the reference for the diagnosis, CMR accurately diagnosed LVNC delineating hyper-trabeculations of the apex and the lateral wall .Hyper-trabeculation with a end-diastolic ratio of non-compacted over compacted myocardium of 2.3 distinguished pathological from non-pathological conditions with a sensitivity of 86% and specificity of 99%   were highly representative of mean global myocardial iron validating current clinical practice .Interestingly, macroscopic fibrosis detected by LGE is uncommon in thalassaemia patients despite current or prior heart failure and across a broad spectrum of myocardial iron loading .Despite significant advances in anti-rejection therapy, acute cellular allograft rejection remains a leading cause of early mortality among transplanted patients. The diagnostic gold standard technique remains repeated endomyocardial biopsy largely limited by insensitivity.CMR can assist the detection of rejection mainly through myocardial T2 relaxation time quantification with sensitivities and specificities approaching 90% except for the early peri-operative period characterised by normal post-operative oedema . A complCardiac involvement by Trypanosoma cruzi infection occurs in 30% of seropositive patients representing a major cause of death from heart failure in Latin America.LGE-CMR typically involves the apical and mid-inferolateral wall in patients with advanced disease but also in asymptomatic seropositive subjects without wall motion abnormalities . IschaemThe most common adverse effect of chemotherapy is cardiotoxicity affecting patient’s prognosis and quality of life independently of the oncological issue. A wide range of agents have been associated with cardiotoxicity, anthracyclines and related compounds being the most frequently implicated.. IncidenWhile echocardiography remains the commonest imaging modality used to follow-up LVEF in patients at risk of developing cardiotoxicity, case series assessing the role of CMR in this setting have raised interesting issues. In a population of patients receiving trastuzumab therapy for breast cancer and developing LV dysfunction, authors reported the presence of sub-epicardial LGE in the lateral wall in all patients as a sign of myocarditis induced by drug toxicity ,132. OthAn optimal nulling of the myocardium is key to LGE interpretation and detection of small areas of fibrosis or quantification of sub-endocardial scars. Although the optimal inversion time can be set based on experience, a single short axis slice can be acquired automatically at different inversion times. The optimal inversion time is then selected visually as the one nulling completely the healthy myocardial signal. According to the underlying suspected pathology, LGE should be acquired before 10 minutes such as in amyloidosis due to the faster washout of gadolinium from blood pool. In cardiomyopathy patients, gadolinium washout can also be faster, needing an earlier acquisition to obtain optimal nulling of the myocardium. This is thought to be related to structural alterations of extracellular matrix associated with reduced myocardial blood flow in DCM patients . Once thLack of ionising radiation, excellent spatial resolution, 3D anatomical assessment and ability to provide tissue characterisation with and without contrast are amongst advantages of CMR making it a valuable and complementary tool to other non-invasive modalities. CMR is recognised as a class I indication for EF, volumes and mass quantification . CMR shoLGE CMR appears highly effective in identifying the aetiology of LV dysfunction in newly diagnosed heart failure and can be used as a safe, clinically effective and potentially economical gatekeeper to coronary angiography in these patients . Safety Whilst CMR offers an excellent morphological evaluation through its high spatial resolution, echocardiography excels through its unique temporal resolution, providing a non-ionising, inexpensive bedside tool, superior for haemodynamic evaluation . Limitations are linked to its restricted lateral spatial resolution, the dependency on good acoustic windows particularly in patients with chronic lung diseases, and the limited assessment of apical segments and the RV. CMR remains partially limited by arrhythmias interfering with ECG triggering and poor ability to perform breath-holds. Metallic non-CMR safe devices and severe renal failure prevent its use.Cardiac computed-tomography (CCT) provides a fast and accurate 3D assessment of coronaries and myocardium in a 30-second time frame even in patients with pacing devices. However, the use of CT remains limited by radiation, renal failure often encountered in heart failure patients (for CT contrast agents), pregnancy and limited assessment of late enhancement still inferior to CMR. It can however be considered as an alternative in patients with pacing devices.Nuclear and CT hybrid devices are rapidly evolving to incorporate high-speed MDCT along with positron-emission tomography (PET) and single-photon emission tomography (SPECT) detector systems.This dual modality imaging presents an opportunity to use a single piece of equipment for a combined assessment of coronary anatomy, perfusion, function and metabolism or coronary calcification. However, radiation exposure as well as availability and cost remain an issue. Table CMR spectroscopy (MRS) and CMR-based molecular imaging have appeared recently as non-invasive tools for assessing myocardial metabolism using the intrinsic properties of nuclei including Phosporus-31, proton, sodium-23, oxygen-17 and 13-carbon . Phospho2)[Newly developed quantitative Oxygen-sensitive CMR techniques have been designed to directly evaluate myocardial oxygen consumption . Elevate2). MBF mea2). Interes2). These gThrough a wide range of sequences, CMR offers a unique non-invasive tool which should be integral part of the clinical work-up of a cardiomyopathy.In vivo tissue characterisation remains a major strength of CMR compared to other non-invasive techniques detecting and distinguishing oedema from fat, fibrosis and myocardial infiltration. Its excellent spatial resolution set it above other imaging techniques to analyse RV mophology and detect RV cardiomyopathies and for identification of regional ventricular hypertrophy or dilatation.Although, CMR provides precious and irreplaceable additional information to standard imaging and invasive methods, it cannot be seen as an alternative to these techniques yet and as a one stop shop but as a unique supplementary method able to characterise abnormal tissue in vivo, allowing pre-clinical detection of disease process and novel parameters for risk stratification.The authors declare that they have no competing interests.All authors contributed to the design and writing of this manuscript. All authors read and approved the final manuscript.


To investigate the usefulness of single-shot spin-echo echo-planar imaging (SSEPI) sequence for quantifying mild degree of hepatic iron stores in patients with viral hepatitis.b-factors of 0 s/mm2 (T2-EPI), 500 s/mm2 (DW-EPI-500), and 1000 s/mm2 (DW-EPI-1000).This retrospective study included 34 patients with chronic viral hepatitis/cirrhosis who had undergone histological investigation and magnetic resonance imaging with T2-weighted gradient-recalled echo sequence (T2-GRE) and diffusion-weighted SSEPI sequence with The correlation between the liver-to-muscle signal intensity ratio, which was generated by regions of interest placed in the liver and paraspinous muscles of each sequence image, and the hepatic iron concentration (µmol/g dry liver), which was assessed by spectrophotometry, was analyzed by linear regression using a spline model. Akaike information criterion (AIC) was used to select the optimal model.P<0.0001). Using the AIC, the regression model for T2-EPI generated by spline model was optimal because of lowest cross validation error.Mean ± standard deviation of the hepatic iron concentration quantified by spectrophotometry was 24.6±16.4  µmol/g dry liver. DW-EPI correlated more closely with hepatic iron concentration than T2-GRE (R square values: 0.75 for T2-EPI, 0.69 for DW-EPI-500, 0.62 for DW-EPI-1000, and 0.61 for T2-GRE, respectively, all T2-EPI was sensitive to hepatic iron, and might be a more useful sequence for quantifying mild degree of hepatic iron stores in patients with chronic viral hepatitis. Abnormalities of iron metabolism are frequently observed in patients with chronic liver diseases such as viral hepatitis, nonalcoholic fatty liver disease, and cirrhosis In recent years, several research groups have reported on the efficacy of iron reduction therapies by phlebotomy Assessment of body iron stores by measurement of serum ferritin concentration has poor specificity Generally, it is accepted that gradient-recalled echo (GRE) sequences are the most sensitive sequence to quantify mild degree of hepatic iron overload Diffusion-weighted (DW) single-shot spin-echo echo-planar imaging (DW-EPI) has become a sequence used routinely in many institutions since the image quality was improved by recent technical progress such as parallel imaging and respiratory triggering We postulate that DW-EPI sequence might be superior to GRE sequence for quantifying mild degree of hepatic iron stores. To our knowledge, the investigation of hepatic iron overload by DW-EPI sequence has not been examined. The aim of this study was to investigate the usefulness of SSEPI sequence for quantifying mild degree of hepatic iron stores in patients with viral hepatitis.The institutional review board (the Ethics Committee of Kurume University) approved this retrospective study , which complied with the principles of the Declaration of Helsinki (2008 version). All included patients gave written informed consent to participate.Our study was targeted at patients with viral chronic hepatitis/cirrhosis and HCC because such patients with chronic liver impairment may have increased liver iron and would have undergone both liver MR imaging and hepatic surgery.a) patients had both chronic viral hepatitis/cirrhosis and HCC; (b) patients underwent abdominal MR imaging with T2-weighted GRE sequence and DW-EPI sequence with b-factors of 0 s/mm2, 500 s/mm2, and 1000 s/mm2 ; and (c) patients underwent an operation for HCC and received a histopathologic diagnosis of either chronic hepatitis or cirrhosis that was based on findings at surgical resection, performed within a month after MR imaging.We reviewed the patients who admitted use of both liver specimens and MR images before hepatic surgery at our institution between January 2007 and April 2008 and identified patients who met the following inclusion criteria: ((a) Available imaging data did not correspond to available histopathologic data because of interval surgery (n = 5), (b) MR studies were incomplete (n = 3), (c) an artifact was observed on MR images and precluded accurate measurement of signal intensity (n = 1), and (d) other causes of chronic liver disease such as alcoholic hepatitis (n = 2) and non-alcoholic steatohepatitis (n = 1). Thirty-four patients formed the final study group . Histopathologic sampling of all patients included in the study was performed after MR imaging . The cause of chronic liver disease was hepatitis C virus infection (n = 26) or hepatitis B virus infection (n = 8). None of the patients had a clinical diagnosis of hemochromatosis that was based on review of medical records.Forty-six patients fulfilled these criteria. Twelve of these 46 patients were excluded on the basis of the following reasons: A partial hepatic resection was performed in all patients with HCC. For each patient, 50 mg of wet liver tissue was extracted from the surgically removed specimen by a MLS1200 MEGA microwave digestion system  for 1 min at 250 W, 1 min at 0 W, 5 min at 250 W, 5 min 400 W, and 5 min at 500 W. For determination of hepatic iron concentration (µmol/g dry liver), the resulting extracts were analyzed by spectrophotometry with a graphite atomic absorption camera  and were converted to the units shown above For histological analysis, fibrosis stage and necroinflammation grade were evaluated semiquantitatively using the METAVIR scoring system Within one month prior to surgery, MR imaging was performed at field strength of 1.5 T  with use of a body phased-array surface coil. A series of DWIs and T2-weighted GRE sequence were obtained using parallel imaging with generalized auto calibrating partially parallel acquisition (GRAPPA) of acceleration factor 2 in all patients. DWI was performed in the transverse plane by respiratory-triggered combining SSEPI sequence with a chemical shift–selective pulse (CHESS). Any antiperistalsis drug was not used.b values of 0 sec/mm2 , 500 sec/mm2 (DW-EPI-500), and 1000 sec/mm2 (DW-EPI-1000); 2170-Hz per pixel bandwidth; 350-mm field of view; 128×88 rectangular matrixes; 9-mm-thick sections; 1-mm intersection gap; six signals acquired; and acquisition time of approximately 1 minute 30 seconds.The imaging parameters for DW-EPI were as follows: repetition time (TR), 2000 msec; echo time (TE), 81 msec; directions of the motion-probing gradient, three orthogonal axes; gradient factor T2-weighted GRE sequence  was performed in the transverse plane by fast low angle shot (FLASH) with one signal acquired during a 22-second breath hold. The imaging parameters for T2-GRE were as follows: TR, 246 msec; TE, 9.5 msec; flip angle (FA), 30°; 350-mm field of view; 9-mm-thick sections; 1-mm intersection gap; 16-number of sections; 256×192 matrix; and 130-Hz per pixel bandwidth.2). The procedure was repeated to measure muscle signal intensity by placing two separate ROIs on the right and left paraspinous muscles in the same slice section used to measure liver signal intensity; care was taken to avoid artifacts such as chemical shifts, magnetic susceptibility, and motion on each sequence.Quantitative image analysis was conducted by measuring the signal intensities of the liver parenchyma and paraspinous muscles. Image analysis was performed by two independent radiologists using plug-in software developed in-house by one of the authors 2). We calculated the liver-to-muscle signal intensity ratio (LMR) by dividing mean liver signal intensity by mean muscle signal intensity for each sequence Muscle signal intensities were recorded as the mean values generated from the two measurements .A Bland-Altman plot was used to analyze the 95% limits of interobserver agreement for the LMR on each sequence The relationship between the LMR on each sequence and hepatic iron concentration was analyzed by means of scatter plots. These results were inspected for linearity and goodness of fit. The relationship between the LMR on each sequence and hepatic iron concentration was modeled by regression techniques using a spline model. Details of spline models are given in the next section.To investigate effects of each LMR on hepatic iron concentration, we applied the linear models containing not only a main term but also knot terms which play a role as an inflection point. The Akaike information criterion (AIC) was used to evaluate these alternate models P<0.05 was considered statistically significant.The Kruskal–Wallis test was used to determine significant differences in the LMR on each sequence among category classification in each histological finding . All analyses were performed using SPSS statistical software . Response and predictor variables are denoted by y and x, respectively. The general form of the univariate (first order) spline model isThe essential point in the use of this spline model is to select the number and location of knots. As used in this paper, one choice for candidates for knots is the quantiles for continuous variables taking into account the sample size. Once one specifies the candidates, the problem turns to the variable selection for predictor variables used in the multiple regression model, which can also be implemented by standard software. One effective method is to use information criteria such as AIC. This kind of modeling Mean ± SD of the hepatic iron concentration quantified by spectrophotometry was 24.6±16.4  µmol/g dry liver. Histological necroinflammation grade was A1 in 21 patients and A2 in 13 patients. Fibrosis stage was F1 in 13 patients, F2 in 4 patients, F3 in 5 patients, and F4 (i.e. cirrhosis) in 12 patients. Steatosis grade was 0 in 14 patients, grade 1 in 11 patients, and grade 2 in 9 patients.There was no significant difference between measurements made by the two observers for the two parameters; the interclass Pearson correlation coefficients were 0.96  for T2-GRE, 0.99  for T2-EPI, 0.97  for DW-EPI-500, and 0.98  for DW-EPI-1000; the mean difference (± standard deviation) was −0.0027±0.054 for T2-GRE, −0.0069±0.052 for T2-EPI, 0.017±0.11 for DW-EPI-500, and 0.013±0.16 for DW-EPI-1000; and the coefficients of repeatability were 0.108 for T2-GRE, 0.105 for T2-EPI, 0.213 for DW-EPI-500, and 0.316 for DW-EPI-1000. Bland-Altman plots with 95% limits of agreement for each sequence are shown in P<0.0001, respectively).The regression analyses showed an excellent overall negative correlation on each sequence. Particularly, T2-EPI correlated most closely with hepatic iron concentration. R square values on each sequence were as follows: 0.75 for T2-EPI, 0.69 for DW-EPI-500, 0.62 for DW-EPI-1000, and 0.61 for T2-GRE +] was chosen as having the best fit, since it had the lowest CV error. The corresponding CV errors were as follows: 14161.3 for T2-GRE, 11357.4 for T2-EPI, 12220.0 for DW-EPI-500, and 14376.2 for DW-EPI-1000.Using the AIC, the linear regression model on T2-EPI [y = 131.0−139.7×LMR+106.5×(LMR−0.73)P values  were as follows: (a) necroinflammation grade: P = 0.4 for T2-GRE, P = 0.89 for T2-EPI, P = 0.68 for DW-EPI-500, and P = 0.6 for DW-EPI-1000; (b) fibrosis stage: P = 0.39 for T2-GRE, P = 0.29 for T2-EPI, P = 0.19 for DW-EPI-500, and P = 0.38 for DW-EPI-1000; (c) steatosis grade: P = 0.75 for T2-GRE, P = 0.77 for T2-EPI, P = 0.69 for DW-EPI-500, and P = 0.95 for DW-EPI-1000.No significant differences were found for the LMR on each sequence among category classification of histological findings . In the present study, we found good correlation between DW-EPI and hepatic iron concentration in patients with chronic viral hepatitis, and also demonstrated that SSEPI sequence was more sensitive than T2-GRE sequence for quantifying small amount of hepatic iron overload; this is in concordance with prior studies reporting a high susceptibility effect with SSEPI sequence A lot of studies have evaluated the correlation between hepatic iron concentration and MRI measurements The sensitivity to iron on T2-GRE sequences varies significantly with various different TE and FA SSEPI sequences are very fast and have a high susceptibility effect, but suffer from limited image quality. This is mostly related to limited signal to noise ratio (SNR), especially at higher b-values, and limited spatial resolution, which constitute an obstacle for its widespread use in clinical practice In the present study, we employed SSEPI sequence with techniques such as parallel imaging and respiratory triggering. This sequence, which has the advantage of high susceptibility effects, was useful to assess mild degree of hepatic iron stores in patients with viral hepatitis. Of DW-EPIs, it was suggested that T2-EPI was the most suitable sequence because DW-EPI-500 and DW-EPI-1000 had loss of SNR caused by application of the motion-probing gradients pulse.In patients with chronic viral hepatitis, steatosis is a common secondary phenomenon. Westphalen et al. b values of 0 sec/mm2, which is not affected to the diffusion signal, for quantifying mild degree of iron stores.On DW-EPI, we found no significant differences in LMR among histological steatosis grades. Use of fat saturation pulse  on DW-EPIs could eliminate the influence of steatosis, which might support the better utility of this sequence for quantifying mild degree of hepatic iron stores. On the other hand, although previous studies reported that liver fibrosis decreased the diffusion signal Several limitations of the present study warrant mention. First, the study was conducted retrospectively and sample size was small. Although a major effort was made to exclude sample bias, there was limited sample size for examination of liver iron concentration using spectrophotometry because of its retrospective nature. Second, all measurements for the LMR were obtained in the right lobe of the liver to avoid motion-related artifact. Because the pathologic specimens were obtained at surgery for an HCC, histologically sampled areas did not completely correspond to radiologically sampled areas. A prospective study with a substantially larger sample is needed to further validate our findings.In conclusion, DW-EPI  was sensitive to hepatic iron, and might be a more useful sequence for quantifying mild degree of hepatic iron stores in patients with chronic viral hepatitis.


Patients with atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin  during an acute episode of AF. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography, which suggests that AF itself influences myocardial blood flow. The present review summarizes the effect of AF on the occurrence of ventricular oxidative stress, redox-sensitive signaling pathways and gene expression, and microcirculatory flow abnormalities in the left ventricle. Angina pectoris is a typical symptom in patients with paroxysmal atrial fibrillation (AF). In most of these patients, angina pectoris is associated with mildly elevated cardiac troponin (cTn) levels suggesting a non-ST-segment elevation myocardial infarction (NSTEMI). However, in a large proportion of these patients, significant coronary artery disease can be excluded by coronary angiography despite clinical symptoms  are generated under physiological conditions in the cardiovascular system and act as second messengers in numerous redox-sensitive signal transduction pathways Figure . HoweverOxidative stress has been implicated as playing a critical role in the pathophysiology of heart and cardiovascular diseases such as heart failure, LV hypertrophy, coronary heart disease, cardiac arrhythmia. It appears that the oxidative events initiate the disease-dependent tissue remodeling and promote its propagation. Oxidative stress is associated with microvascular flow abnormalities and occurs immediately after new-onset AF likely representing key initiator mechanisms of AF-related ventricular remodeling. This has been shown in patients with lone recurrent AF and for rapid atrial pacing models  and endothelin (ET) play important roles in the regulation of cardiovascular function as well as in the pathogenesis of heart and cardiovascular diseases. AF has been associated with increased plasma and tissue levels of angiotensin II (AngII)  have been shown to increase NO availability and it is possible that this effect is mediated by a stronger ANG-II-dependent activation of AT2+-waves via IP3-dependent Ca2+-release leading to DAD  exerts its proarrhythmogenic effects by two different ways. First, due to its strong vasoconstrictory activity, ET-1 may induce ischemia which facilitates arrhythmia. Second, upon binding to endothelin receptor A (ET-A), ET-1 affects intracellular calcium handling and, in particular, provokes intracellular CaHeart failure , the expression of six homologs  has been identified  in pigs , glycogen synthase kinase 3β (GSK-3β), muscle isoform of glycogen phosphorylase (PYGM), and acyl-coenzyme A dehydrogenase (ACADL; Bukowska et al., It is fully established that even mild ischemia is associated with compromised mitochondrial function and requires metabolic adaption to maintain adequate ATP generation and cardiac output (Shohet and Garcia, AT induces oxidative stress in the atrial and ventricular myocardium. In the ventricles, AF causes alterations in gene expression and activation of specific signal transduction pathways. As a consequence, microcirculation is impaired, troponin can be released, which is associated with causing clinical symptoms like angina pectoris and dyspnea. It remains to be determined if these alterations are also related to the increased rate of death in AF patients shown by several epidemiologic studies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.