We attempted to clarify myocardial telomere dynamics using samples from 530 autopsied patients using Southern blot analysis. Overall regression analysis demonstrated yearly telomere reduction rate of 20 base pairs in the myocardium. There was a significant correlation between myocardial telomere and aging. Moreover, regression analyses of telomere and heart weight yielded a telomere reduction rate of 3 base pairs per gram, and a small but significant correlation between telomere reduction and heart weight was demonstrated. Hearts of autopsied patients who had died of heart disease were significantly heavier than those of patients who had died of cancer or other diseases, and heart disease was significantly more correlated with myocardial telomere shortening than cancer or other diseases. Here we show that telomeres in myocardial tissue become shortened with aging and heart disease, and that heart disease was associated with a gain of heart weight and telomere shortening in the myocardium. Normal human cells exhibit a limited capacity for proliferation in culture2We previously demonstrated that the yearly telomere reduction rate in 168 samples of myocardium from the anterior wall of the cardiac left ventricle was 13 base pairs, being similar to that in other human tissues and organs78Accordingly, in the present study using Southern blotting, we measured telomere in samples of myocardial tissue from a large sample of 530 autopsy cases covering a wide age range, from neonates to centenarians. Particular attention was paid to yearly telomere reduction rates in this large number of myocardium samples. Moreover, we analyzed the relationship between myocardial telomere and heart weight for major causes of death among the individuals examined.HinfI (+) and non-digested genomic DNA (−) from 8 samples employed for verifying the process of digestion, including molecular size markers. p < 0.001) and 14 (p = 0.125) base pairs per year for these two sets of subjects, respectively. The data indicated a significant age-related telomere length reduction in the myocardium for the 530 subjects overall, whereas the significance was only marginal for the 504 subjects aged 60 years or older. The data in p = 0.001) and 0.2 (p = 0.033) base pairs per unit heart weight (gram) for these two sets of subjects, respectively. The data indicated a small but significant correlation between myocardial telomere length and heart weight.p < 0.001) or other diseases (p < 0.001).p = 0.021, p = 0.017). However, myocardial telomeres in subjects who had died of heart disease were not significantly shorter than in those who had died of other diseases .In previous studies, we have investigated the rates of telomere length reduction in 15 types of human cells, tissues and organsIn the present study, therefore, we used Southern blotting to measure telomeres in a larger cohort of samples of quiescent myocardium from 530 autopsied individuals with a wide age range, from neonates to centenarians. Using regression analysis, we were able to demonstrate that the telomere reduction rate in the myocardium was 20 base pairs per year, and that there was a significant correlation between myocardial telomere and age.Telomere reduction in the myocardium would be expected because fibroblasts and endothelial cells can undergo mitosis; but clearly this would not exert a major influence at the tissue levelIn our study cohort, we found that telomeres in the myocardium became shorter with aging and heart disease. Although the significance of the correlation between myocardial telomere length and heart weight was small, it was more significant in subjects who had died of heart disease than in those who had died of cancer. We found that heart disease was associated with heart weight gain and telomere shortening in the myocardium.Although from the 1920s it had been assumed that myocardial tissue is terminally differentiated and unable to undergo mitosis, recent years have seen a change in this viewpoint due to the discovery of myocardial cell division in the adult heart, and a net loss of total myocardium can be observed during physiological aging14151819Although cardiac hypertrophy contributes to a gain in heart weight, there has been no evidence that this involves an increase in the number of cardiac cells. In the present study, however, we found that heart disease was associated with myocardial telomere shortening, thus supporting the possibility that that myocardium might regenerate and proliferate within the human lifespan as a result of heart disease or injury. However, any such regeneration might likely be limited to very slow myocardial replacement and growth. However, various attempts to regenerate the injured heart using cardiac stem cells, cellular reprogramming and tissue engineering are currently in progress212223The study protocol was approved by the Tokyo Metropolitan Institute of Gerontology Ethics Committee. Family members of all autopsied subjects gave written consent for educational and scientific use, including DNA analysis, of the subjects' organs. All experiments involving the handling of human tissues were performed in line with tenets of the Declaration of Helsinki.After death, all the subjects were kept refrigerated at 4°C until autopsy. Tissues adjacent to all the sampled areas were examined histologically by specialists in anatomical and surgical pathology , and any tissues showing marked accumulation of inflammatory cells and/or autolysis were not included. Samples showing myocarditis were also avoided. Data on age and cause of death for the 530 subjects, who underwent autopsy at the Tokyo Metropolitan Geriatric Hospital and the Japanese Red Cross Medical Center, are shown in HinfI ; complete cleavage was confirmed by electrophoresis of the DNA digests on 0.8% agarose gels. Fractionated DNA fragments were transferred to nylon membranes  by an alkaline transfer technique using capillary blotting, followed by hybridization for 12 h at 50°C in an appropriate solution  with a (TTAGGG)4 probe labeled with [γ-32P]ATP (Amersham) at the 5′ end with T4 polynucleotide kinase . Membranes were washed in 2 × SSC  at room temperature and then in 6 × SSC, 0.1% SDS, at 50°C for 15 min while being shaken. Subsequently, they were dried with filter paper and then exposed to Fuji Imaging Plates  for 3 h at room temperature. Analysis was conducted with a BAS-2500 Mac image analyzer (Fuji Photo Film), employing the programs Image Reader  and Mac Bas . In this study, we used Telomeric software version 1.2  to assess the sizes and distribution TRF5DNA extraction and Southern blotting was performed by A.I. and K.N., who were blinded to data about age, cause of death and heart weight of the 530 autopsied subjects. Genomic DNA was prepared from each sample by treatment with proteinase K and sodium dodecyl sulphate (SDS), followed by repeated phenol-chloroform extraction. In preliminary experiments with genomic DNA from all samples, pulse-field gel electrophoresis was performed using 1.0% agarose gels and the Genofield system , a biased sinusoidal field gel electrophoresis system that is able to examine autolytic changes after death. Only DNA more than 100 kilobase pairs (kbp) in length was assayed in this study. Aliquots of 5 μg were digested with the restriction enzyme t test and correlations by Fisher's test, using the methods reported in many previous studies of annual telomere reduction rates in myocardiumDifferences in mean values were assessed for significance by Student's M.T. and K.T.: Conception and design, Data analysis and interpretation, Manuscript writing, Final approval of manuscript. N.I.-S., J.A., N.I., A.I. and K.N.: Collection and/or assembly of data, Data analysis and interpretation. M.S., T.A., M.F. and K.T.: Provision of study material or patients, Histological examination.Supplementary information


Matrix metalloproteinases play a role in regulating cardiac remodeling. We previously reported an association between tissue inhibitor of metalloproteinase 2 (TIMP-2) expression and mitral valve (MV) disease. However, the determinants and prognostic value of mitral TIMP2 after MV surgery are unknown.This retrospective study of 164 patients after MV surgery in a tertiary medical center in Taiwan assessed mitral TIMP2 on a semiquantitative scale (0–2) by immunohistochemical staining. The primary endpoints were the composite of cardiovascular death and heart failure admission.Mean age was 50.4±13.7 years. After a mean follow-up period of 101±59 months, primary endpoints had occurred in 25 (15.2%) subjects. Patients with and without primary endpoint events significantly differed in terms of age  and left ventricular end-systolic diameter (LVESD)  at surgery. The TIMP2 had a significant dose-dependent association with development of a primary endpoint (p = 0.002). Kaplan–Meier analysis showed that TIMP2 expression has a significant positive association with primary endpoint-free survival . Cox regression analysis showed that independent predictors of primary endpoints were TIMP2 , age  and LVESD .The lack of mitral TIMP2 expression is associated with increases in cardiovascular death and heart failure following MV surgery. Tissue turnover plays an important role in the operational longevity of heart valves. The clinical and histopathological features of mitral valve (MV) diseases indicate that matrix degradation and remodeling may be important factors in their severity. Matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) contribute to tissue remodeling in several physiological and pathological states Mitral valve surgery can repair valve damage but cannot correct the underlying causes of degenerative disease. Thus, progression of the disease and degradation of the mitral structure due to matrix degeneration may cause late complications. Expression of TIMP2 reportedly stimulates fibroblast growth in the MV This study continues our earlier studies of risk factors for MV disease This cross-sectional study retrospectively reviewed the medical files of 164 patients who had received MV surgery at Kaohsiung Medical University Hospital, a tertiary medical center in Taiwan, between June 1, 1991 and November 31, 2006. Baseline data collection for each patient included gender, age, disease duration from symptom onset to surgery, and possible underlying predisposing factors for MV disease, including history of infective endocarditis, MV prolapse, rheumatic heart disease (RHD), major MV disease type , hypertension, atrial fibrillation, and pulmonary edema. The study was approved by the institutional review board of Kaohsiung Medical University Hospital (KMUH-IRB-960288). According to the local law, no informed consent is required to perform this type of analysis after decoding data.Mitral valve disease was diagnosed according to standard echocardiographic methods and surgical findings. Left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were determined by transthoracic echocardiography based on criteria established by the American Society of Echocardiography. The echocardiograph readers were blinded to all baseline patient data.2O through graded alcohol. Antigen retrieval was enhanced by autoclaving slides in sodium citrate buffer (pH 6.0) for 20 minutes. Endogenous peroxidase activity was quenched by five-minute incubation in 3% hydrogen peroxide. The slides were then incubated with primary human TIMP-2 affinity purified polyclonal antibody  at a dilution of 1∶50 for 1 hour at room temperature The results were independently evaluated by an experienced pathologist blinded to all clinical data for the patients. The tissues were obtained from the excised anterior mitral cusp during replacement. Representative tissues were sectioned into blocks , deparaffinized with xylene, and rehydrated into distilled HAll data were expressed as mean ± standard deviation. In group comparisons, a chi-square test was used for categorical variables and Student t test was used for continuous variables. The primary outcomes were the composite of cardiovascular death and admission for heart failure. Linear-by-linear association analysis was conducted to find the dose-dependent influence of TIMP2 expression on the occurrence of primary outcomes. Cumulative curves constructed by Kaplan-Meier test were compared by log-rank test. The hazard ratios (HRs) for the primary endpoints were obtained by univariate and multivariate Cox regression analyses. Receiver operating characteristic (ROC) curves were constructed to illustrate the discrimination threshold of continuous variables for the occurrence of primary endpoints. Accuracy is measured by the area under the ROC curve. The Statistical Package for the Social Sciences (SPSS) 11.0 for Windows  was used for all statistical analyses. All tests were 2-sided, and a p value less than 0.05 was considered statistically significant.The analysis included 164 patients who had received MV surgery. After a mean follow-up period of 101±59 months, primary endpoint events occurred in 25 (15.2%) subjects, including 6 cardiovascular death and 19 admission for heart failure.The baseline characteristics between patients with and without primary endpoint events were shown in Comparisons of mitral TIMP2 expression revealed expression grades 0, 1, and 2 in 14, 107 and 43 patients, respectively. Mitral TIMP2 staining was associated with LAD, LVEDD, severity of MR, and history of the following: RHD, infective endocarditis, chordae tendinae rupture, atrial fibrillation, fever, major mitral disease, LAD, and LVEDD. The TIMP2 staining grade correlated negatively with occurrence of primary endpoints (p = 0.001) . ExpressThe Kaplan-Meier curves were constructed to compare the three grades of mitral TIMP2 expression in terms of primary endpoint events, cardiovascular death and admission for HF  .Cox regression analysis was shown in This study had three major findings. First, mitral TIMP2 staining intensity was associated with the occurrence of primary endpoints, death and HF admission after MV surgery. Second, mitral TIMP 2 staining had a grade-dependent effect on the occurrence of primary endpoints. Third, there was a significant association of TIMP2 expression with the occurrence of primary endpoints even after adjusting the co-variables, including age and LVESD, both of which were also independent predictors of the primary endpoints in this study.Valvular tissue degeneration is characterized by fibrosis and calcification, which can cause valve dysfunction. The TIMP2 can trigger the signal cascade that instigates cardiac fibrosis, which is a characteristic of MV degeneration. The TIMP2 is also believed to act through specific, high-affinity receptors and through links to G protein and cAMP signaling pathways Animal models have also shown the direct causal roles of TIMP2 activity in left ventricular (LV) remodeling. Heymans et al. showed that mRNA and protein levels of TIMP2 correlate with intra-cardiac fibrosis development Replenishing TIMP2 in diseased myocardium has shown potential as a therapeutic treatment for reducing or preventing disease progression Age-dependent changes in LV structure and function may partially result from alterations in TIMP2 expression. Whereas this study showed that age is an independent risk factor for the development of primary endpoints, a previous study found thatTIMP-2 level changes as age increases Another independent predictor of the primary endpoints in this study was LVESD. Previous animal studies have found that, as the LV ejection fraction improves, ventricular remodeling is associated with reduced LVESD and reduced TIMP2 expression, which is consistent with our findings Some limitations of this study are noted. First, this retrospective analysis of a single-center sample was subject to selection bias. Second, TIMP2 expression in tissues was not examined simultaneously with fibrosis-related parameters. Therefore, this study did not determine whether TIMP2 expression is simply a reactive response or a contributing factor in ventricular remodeling. However, this longitudinal study found that TIMP2 has potential use as a prognostic parameter. Third, this study only measured mitral expressions of matrix proteinases. Ventricular expression of proteinases may differ pathologically. However, since the mitral valve and ventricle have the same embryonic origin, they may have similar pathological characteristics. Fourth, proteinase expression was measured only by immunohistochemical analysis. The findings of this require further confirmation by additional measurements such as polymerase chain reaction. Fifth, the findings should be limited to the association of a biomarker with the clinical outcomes because there is no mechanism insight from the current findings. Therefore, the preliminary findings should be replicated if possible.Mitral TIMP2 staining proved to be an effective grade-dependent prognostic indicator associated with HF admission and death from MV surgery. These findings suggest that TIMP2 is a potential target for therapeutic intervention in MV disorder after MV surgery.


Caloric restriction increases plasma non-esterified fatty acid (NEFA) levels, and increases myocardial triglyceride content. It has been shown that elevated levels of NEFA’s in patients with metabolic disease (metabolic syndrome/ type 2 diabetes mellitus) are associated with a decrease in left ventricular function. However little is known about its effects on right ventricular function. Therefore, the purpose of the present study was to evaluate myocardial metabolic flexibility in relation to right ventricular diastolic function in healthy volunteers after short-term caloric restriction.Measures were performed in 14 healthy subjects before and after 3 days of caloric restriction based on Modifast diet  using cardiovascular magnetic resonance imaging (MRI). Myocardial triglyceride (TG) content was measured in the interventricular septum using navigator gated, proton MR spectroscopy. After water suppression, myocardial TG content was quantified as a percentage of the unsuppressed water signal. Right ventricular diastolic function was measured using MR velocity mapping across the tricuspid valve. Early (E) deceleration rate was quantified and regarded as representative for right heart diastolic function.Caloric restriction increased plasma fatty acid levels from 0.53 ± 0.30 mmol/L at baseline to 1.14 ± 0.39mmol/L after caloric restriction. Concomitantly, myocardial TG content increased from 0.38 ± 0.19 % to 0.59 ± 0.24 % (P< 0.01). These changes were associated with a decrease in right ventricular diastolic function (E deceleration rate) from -1.79 ± 0.50 ml/sec2 x 10-3 to -1.25 ± 0.37 ml/sec2 x 10-3 (P< 0.01), example is shown in figure Short-term caloric restriction in healthy volunteers increases myocardial triglyceride content and is associated with decreased right ventricular filling properties. The underlying pathophysiological mechanism may be involved in the development of global cardiac dysfunction in metabolic disease, such as obesity and diabetes type 2 related diseases.None.


Positron Emission Tomography (PET) can quantify myocardial oxygen consumption  and myocardial ischemic dogs (n=3). The later dogs includes 70% (n=1) and 100% (n=2) area stenosis in the second diagonal branch of the left descending coronary artery (LAD). The 17O blood tracer was prepared using artificial blood perfluorodecalin emulsion or PFD  and 70% enriched 17O2 gas. Each dog was injected 2 mL/kg 17O-PFD at rest within 30 sec. A novel CMR T1ρ-weighted imaging was performed at baseline and then to monitor the myocardial T1ρ signals for over 30 min after the injection. The 17O2 gas absorbed in PFD will be taken up by the myocardial tissue and converted into H217O water, which will be detected by T1ρ-weighted imaging with a negative contrast. The H217O water concentration can be obtained with the ratio between T1ρ-weighted signals after and before the 17O-PFD injection. MVO2 can be quantified using a new model developed in our laboratory. Quantitative perfusion CMR imaging was also performed at the end of study to confirm the ischemic area.The initial 2 in the anterior myocardial region of three normal dogs was 3.96 ± 0.97 μmol/g/min, which agrees well with MVO2 measured by PET in mongrel dogs. For the 70% stenotic dog, the MVO2 was 2.84 μmol/g/min in the anterior region  and 1.57 μmol/g/min in the lateral region , respectively (Figure The averaged MVO17O-CMR may have potential to provide a direct and non-invasive measurement of the oxygen consumption to facilitate comprehensive evaluations of patients at molecular level with a variety of pathophysiological etiologies.The


Numerous studies show the benefits of cardiac rehabilitation in patients with coronary artery disease. Nevertheless, the effects of regular exercise on myocardial function are still controversial.This study aimed to evaluate the effects of aerobic exercise of moderate intensity, performed in patients after a first myocardial infarction on cardiac function by cardiac magnetic resonance.Twenty-six male patients, 52.9 ± 7.9 years, after a first myocardial infarction were assigned in two groups: 18 in trained group (TG) and eight in control group (CG). The TG performed supervised aerobic exercise on treadmill at 50 to 70% of heart rate reserve, twice a week. The groups were followed for at least three months. Laboratory tests, anthropometric measurements, exercise test and cardiac magnetic resonance were conducted before and after intervention. Statistical analysis was performed using the nonparametric tests with a significance level of 5%.After intervention, there was a statistically significant reduction of 10.8% in fasting blood glucose in TG (p = 0.011). There was a statistically significant increase in weight and body mass index of the CG (p = 0.0391). There was a statistically significant increase in oxygen consumption obtained indirectly in the treadmill exercise test only in the TG . The chronotropic index had a statistically significant increase (p = 0.0432) of 12.65% in GT and did not change in CG. The Duke score showed statistically significant difference (p = 0.001) in values obtained in the TG, with the initial score of 6.9 ± 5.2 and final of 10.9 ± 4.1. These same trends were not found in the CG. Cardiac magnetic resonance showed a statistically significant reduction in ventricular mass from 128.7 ± 38.9 to 117.2 ± 27.2 g in TG (p = 0.0032). There was a trend to increase of left ventricle end diastolic volume (LVEDV) in both groups. No significant change occurred in left ventricle ejection fraction in both groups. The relation LV mass/LVEDV reduced from 1.29±0.36 to 1.05±0.22 g/ml.It was observed that aerobic exercise of moderate intensity improved physical capacity and other cardiovascular variables, and identified a trend to a positive remodeling in the trained group, where the increase in left ventricular diastolic dimension was not associated with increased in ventricular mass.


Cardiac complications mainly related to myocardial iron overload (MIO) remain the main cause of morbidity and mortality in thalassemia major (TM). Thalassemia cardiomyopathy is treatable and partly reversible if appropriate chelation therapy is instituted in time. The validated multislice multiecho T2* Cardiovascular Magnetic Resonance (CMR) technique has permitted to quantify segmental and global myocardial iron burden detecting different patterns of iron overload. Aim of our study was to verify the risk of cardiac complications related to different patterns of MIO in a large cohort of TM patients.We considered 812 TM patients for who CMR and cardiac data were collected in a central data base. Three short-axis views  of the left ventricle were acquired using a multislice multiecho T2* sequence. Using a previously validated software the 16 segmental T2* values and the mean global heart T2* value were provided. A conservative cut off of 20 ms was considered the limit of normal for the segmental and global T2* values.We identified 4 groups of patients: group I (17%) with homogeneous MIO , group II (12%) with heterogeneous MIO (some segments with T2*<20 ms and others with T2*≥20 ms) and global heart T2*<20 ms; group III (29%) with heterogeneous MIO and global heart T2*≥20 ms; group IV (42%) with no MIO . The percentage of patients with cardiac complications was significantly different in the 4 groups . In particular, the percentage of patients with heart failure was significantly different in the 4 groups . No significant differences were found among groups in the percentage of arrhythmias and pulmonary hypertension. Odds Ratio for cardiac complications was 1.7  for patients with homogeneous MIO vs patients with no MIO. Odds Ratio for heart failure was 2.3  for patients with homogeneous MIO versus patients with no MIO and 2.2  for patients with heterogeneous MIO and global heart T2*<20 ms versus patients with no MIO.Homogeneous MIO predicts a significantly higher risk to develop cardiac complications, especially heart failure, suggesting an intensive chelation therapy in this group of patients.“No-profit” support by industrial sponsorships  and “Ministero della Salute, fondi ex art. 12 D.Lgs. 502/92 e s.m.i., ricerca sanitaria finalizzata anno 2006” e “Fondazione L. Giambrone”.


RV restriction (including presystolic pulmonary A wave) [Acute cor pulmonale (ACP) is associated with increased mortality in patients ventilated for acute respiratory distress syndrome (ARDS). Interventional lung assist (iLA) allows a lung-protective ventilatory strategy, whilst allowing CO A wave)  is not rA prospective analysis of retrospectively collected data in patients with echo during iLA was performed. Data included epidemiologic and ventilatory factors, LV/RV function, evidence of RV restriction and pulmonary hemodynamics. Data are shown as mean ± SD/median (interquartile range).P = 0.005), a worse PaO2:FiO2 ratio (9.4 (7.8 to 12.6) vs. 15.2 (10.7 to 23.9), P = 0.009) and higher pulmonary artery pressures (56.5 mmHg (50 to 60) vs. 44.5 (40.5 to 51.2), P = 0.02). No echo features of ACP were found, with no significant difference between RV systolic function, pulmonary acceleration time and pulmonary velocity time integral between survivors and nonsurvivors. The incidence of RV restriction was high (43%), and independent of PHT, RV systolic function and level of respiratory support, but correlated with CO2 levels (restrictive 7.1 kPa (7.4 to 8.0) vs. 6.1 (5.8 to 6.8), P = 0.03). See Figure Thirty-two patients 45 ± 17 years), 22 male (68%), SOFA score 11.15 ± 2.38 were included. Pulmonary hypertension (PHT) was 53%, and hospital mortality 43%. Mortality was not associated with age, days on iLA, length of ICU stay, inotropic support, nitric oxide or level of ventilatory support, but was associated with pressor requirement (7 years, Typical echo features of ACP were not seen in this study, possibly because of the protective ventilatory strategies allowed by use of iLA. The incidence of RV restriction may reflect more subtle abnormalities of RV function. Further studies are required to elucidate RV pathophysiology in critically ill adult patients with ARDS.


Objectives. The aim of this study was to investigate the occurrence of myocardial injury in critically ill children through assessment of cardiac troponin T levels and whether levels are associated with disease severity and myocardial dysfunction measured by echocardiography. Methods. Over a 6-month period, this case control study included 50 patients admitted to Pediatric Intensive Care Unit of Zagazig University Children's Hospital. Twenty-five healthy children were included as a control group. Demographic and clinical data including the pediatric index of mortality II score were recorded. Echocardiographic examination was done and level of cardiac troponin T was measured using Elecsys Troponin T STAT Immunoassay. Results. Cardiac troponin T levels were significantly higher in critically ill in comparison to healthy children (median 22 (18–28) pg/mL versus 10 (10-10) pg/mL, P < 0.05). Cardiac troponin T levels correlated positively with duration of ventilation as well as with disease severity and correlated negatively with left ventricular fractional shortening. Moreover, cardiac troponin T levels were significantly higher in nonsurvivors when compared to survivors (median 34.5 (27.5–41.5) pg/mL versus 20 (18–24) pg/mL, P < 0.05). Conclusion. In critically ill children, cardiac troponin T levels were elevated and were associated with duration of ventilation and disease severity. Cardiac troponins I and T are regulatory proteins that control the calcium-mediated interaction of actin and myosin, producing myocardial contraction . Since tAn unexpectedly high incidence of clinically unrecognized myocardial injury, assessed by elevated cardiac troponin I levels, has previously been reported in critically ill adult patients .Elevated cardiac troponins levels have been detected in children critically ill with congenital heart disease before and after cardiac surgery . In patiTo our knowledge, there is no published data concerning myocardial injury in PICUs in our country. So, the aim of this study was to evaluate myocardial injury in critically ill children in our PICU and to assess relation between cardiac troponin T (cTnT) levels and disease severity as well with myocardial dysfunction measured by echocardiography.The study was conducted prospectively as a case control study within the Zagazig University Children's Hospital PICU, from June 2012 through December 2012. Patients were included with age from >1 month to 12 years, of different admission etiologies other than congenital or acquired heart diseases. Patients with abnormal renal function were excluded from the study.Twenty-five age and sex matched healthy children with no history of critical illness or chronic disease coming for elective specific general surgery and having routine outpatient phlebotomy were included as a control group.Informed consent was obtained prior to inclusion in the study from the children's guardians. The study protocol was approved by the Pediatric Committee in Zagazig University.Demographic and clinical data were recorded, including age, diagnosis, pediatric index of mortality II (PIM II) score, and outcome. Laboratory investigations included complete blood count, C-reactive protein, arterial blood gases, renal function, and measurement of serum cTnT level.Samples were obtained on admission to PICU. Samples were spun, separated, and frozen at −20°C until batch analysis was performed. The assay was done with an Elecsys 1010 System Analyzer using the Elecsys Troponin T STAT Immunoassay  ., and Doppler echocardiography. The left ventricular end systolic diameter, left ventricular end diastolic diameter, ejection fraction, and fractional shortening were measured using M-mode echocardiography in the left parasternal view.All patients and controls underwent echocardiographic examination to assess the cardiac functions on the same day where the blood samples for cTnT were obtained. Echocardiography was performed at the bedside using GE vivid-7 multipurpose system with different probe sizes. Each patient was examined according to the recommendations of the American Society of Echocardiography . EchocarP value of <0.05 was considered statistically significant.Data were analyzed using Statistical Package for Social Sciences (SPSS) release 16. Nonparametric value represented as median and interquartile range (IQL) and the median of two groups was tested by Mann-Whitney test. Qualitative data are represented by frequency and relative percentage and chi-square test was used for testing association of qualitative data. Correlations were performed using Spearman's rank correlation. In all analyses, During the study period, 50 critically ill children were included in the study. Details of the baseline characteristics are given in P < 0.05; P < 0.05).There was highly significant increase in the serum level of cTnT in the critically ill children in comparison to the control group (median 22 (18–28) pg/mL versus 10 (10-10) pg/mL, During their ICU stay, 26 (52%) patients required mechanical ventilation. Overall mortality was 32% (16 of 50 patients). There were highly significant positive correlations between the level of cTnT and the duration of ventilation as well with PIM II score and highly significant negative correlation with the fractional shortening .P < 0.05; As regards relation between cTnT and outcome, nonsurvived children had higher cTnT levels when compared with survivors (median 34.5 (27.5–41.5) pg/mL versus 20 (18–24) pg/mL, Acute severe myocardial dysfunction remains a significant cause of mortality and morbidity in children requiring intensive care . In thisThis prospective study showed that critically ill children had significantly higher level of cTnT when compared with healthy children. The same finding was documented in Clark et al. study  which inIn ICU patients, physiologic stresses can occur in the form of either increased myocardial oxygen demands  or decreased myocardial oxygen delivery  resulting in cardiac dysfunction, cardiac injury, or both . This poIn our study, cTnT levels were positively correlated with the duration of ventilation. Trevisanuto et al.  found siIn the current study, there were highly significant positive correlations between the level of cTnT and PIM II score as a measure of disease severity. Clark et al.  and FentAs regards echocardiographic data, the current study revealed a highly significant negative correlation between levels of cTnT and left ventricular fractional shortening. In preterm neonates, El-Khuffash et al.  stated tResults of our study also showed that there was highly significant difference between levels of cTnT in cases who died and those who survived, being higher in nonsurvivors. This finding was in agreement with that of Spies et al. study  in whichMyocardial injury, detected with elevated cTnT levels, occurs in critically ill children. CTnT levels correlated significantly with disease severity and left ventricular systolic functions. An association between mortality and elevated cTnT levels was found.


Exercise stress testing is the most physiological method of inducing myocardial stress, but its application to clinical and scientific CMR has been limited because of problems arising from cardiac and respiratory motion during stress. Under pharmacological stress, left ventricular strain measurement abnormalities by CMR have been demonstrated to be earlier and more sensitive markers of contractile dysfunction than global left ventricular ejection fraction or development of regional wall motion abnormalities alone. There are several validated methods of measuring myocardial strain. A recently proposed method is feature tracking (FT), which has advantages over other methods in having shorter acquisition and analysis times and not requiring additional scanning as the features are tracked from the clinically standard cine steady-state free precession (SSFP) sequences. This offers a potential method to assess myocardial strain during exercise stress.Seven healthy volunteers without known cardiovascular disease gave informed consent and enrolled for supine cycle ergometry on the CMR scanner table . Subjects underwent a standardised incremental exercise protocol. Imaging included a standard short-axis stack of cine SSFP images from the cardiac base to apex, on a 3T Philips Achieva TX® system using a 32-channel multi-transmit coil. Scan parameters included slice thickness of 10mm, repetition/echo time of 2.4/1.21ms, flip angle 40°, 9-11 slices, with 20 phases per slice.For this study, only the mid LV-slice was analysed. Diogenes CMR FT software  was used for strain analysis. This was based on contours manually drawn along the LV endocardial border of one frame, with the software automatically propagating the contour and following its features throughout the remainder of the imaged phases. Software-derived parameters include circumferential epicardial and endocardial, longitudinal, and radial tissue velocity, strain, strain rate and time to peak strain.Seven subjects (average age 39.4 years) underwent exercise stress. Table Feature tracking can be used to quantify circumferential and radial strain during cycle ergometer exercise stress in healthy volunteers. It provides a potential method for assessing deformation parameters in patients with coronary as well as structural heart disease.The authors are supported by Clinical Research Training Fellowships from the British Heart Foundation; as well as the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust.


Clinical Journal of Sports Medicine in 2009, we studied subjects that differed in terms of age and training status and assessed the impact of prolonged exercise on systolic and left ventricular diastolic function and cardiac biomarkers levels, recognized as identifiers of cardiac damage and dysfunction. We also assessed the possible influence of event duration, exercise intensity and weight loss (dehydration) on left ventricular diastolic function.In this research, an extension to our previous work published in the Ninety-one male cyclists were assessed by echocardiography and serum biomarkers before and after the 2005 Quebrantahuesos cycling event (206 km long and with an accumulated slope of 3800 m). Cardiac function was assessed by echocardiography and cardiac biomarkers were assessed in blood serum. Echocardiograms measured left ventricular internal dimension during diastole and systole, left ventricular posterior wall thickness during diastole, interventricular septum thickness during diastole, left ventricular ejection fraction and diastolic filling. The heart rate of 50 cyclists was also monitored during the race to evaluate exercise intensity. Echocardiograph results indicated that left ventricular diastolic and systolic function decreased after the race, with systolic function reduced to a significant degree. Left ventricular ejection fraction was below 55% in 29 cyclists. The decrease in left ventricular systolic and diastolic function did not correlate with age, training status, race duration, weight loss or exercise intensity.Left ventricular systolic and diastolic function was reduced and cardiac biomarkers were increased after the cycling event, but the mechanisms behind such outcomes remain unclear. This study is a further analysis of data collected for a previous work . One potSpecific exercise parameters (training status and exercise intensity and duration) that may affect observed changes in biomarkers and ventricular systolic and diastolic function are poorly described and the mechanisms involved are not well understood. To the best of our knowledge, the influence of exercise intensity on left ventricular function has not yet been determined, as we were unable to locate any studies of ventricular dysfunction in cyclists of different ages and training levels for a long-duration cycling event (6 hours or more). Therefore, for a long-duration cycling test, we studied, following a similar study , the infThe study protocol was approved by the Research Ethics Committee of the Government of Aragón (Spain). Amateur male cyclists scheduled to participate in the 2005 Quebrantahuesos Cycle Race (UCI Golden Bike series) were invited to participate in the study via the official race organizer’s website . The firSubjects completed a general questionnaire, to ascertain personal and cycling history, and a log referring to cycle training in the previous 6 months 4358 ± 1731 km). Cyclists were assessed the day before, and approximately 20 minutes after, the cycling event 731 km. C, consumpPre- and post-race assessment of the 91 cyclists included the following: echocardiography, body mass, heart rate (HR), and blood pressure measurements and a 12-lead electrocardiogram. HR for 50 of the cyclists was also measured during the race using a Polar HR monitor  and the data was downloaded using Polar Precision Performance software (version 3.0) . FinallyParticipants underwent a resting echocardiographic examination in the left lateral decubitus position. One experienced sonographer performed all the measurements using a commercially available system (ATL ultrasound HDI 5000) and a 2.5 MHz phased array transducer. Two-dimensionally guided M-mode echocardiograms were obtained from the left parasternal long-axis view. These recordings, made according to American Society of Echocardiography recommendations , were usProcedures were as described in the previous work published . The uppStatistical analyses were performed using SPSS version 14.0. Data were expressed as means and standard deviations. Paired student’s t-tests were used to determine differences between pre- and post-race mean values for the various echocardiographic parameters. Analyses for non-Gaussian distributed variables were performed using the Wilcoxon test for paired samples.P < 0.05.Pearson and Spearman correlation coefficients were calculated as standard. Multivariate linear regression was used to assess the relationships between left ventricular diastolic function — measured as the dependent variable — and age, weight loss, training status, event duration and exercise intensity as independent predictors. The level of significance was set to P < 0.001) [P < 0.001) [All 91 cyclists lost weight  was 67.7 ± 8.2 and the mean E/A ratio was 1.6 ± 0.4.P < 0.001) and, in 29 cyclists, post-race LVEF was below 55%.The cycling event exercise resulted in decreased LVIDd and increased LVIDs in the participants but produced no change in the LVPWd or IVSDd Table . The LVE2 = 0.147, P = 0.267; diastolic: R2 = 0.091, P = 0.599).Early transmitral diastolic filling velocities were reduced and late transmitral diastolic filling velocities were increased, resulting in a reduced E/A ratio Table . The posPost-race cTnI and NT-proBNP levels were significantly raised, with 43% of participants exhibiting cTnI levels above 0.04 μg L-1 and with 65% of the participants exhibiting NT-proBNP levels above 125 ng L-1 [The results of this study confirm those of previous studies (running and ironman) in demonstrating that prolonged strenuous exercise reduces systolic and diastolic function ,21,28-30The decrease in post-race LVEF supports the suggestion that systolic changes only develop during long-duration events ,21,32,33No previous studies have been conducted for amateur cyclists of different ages and training levels or for long-duration cycling events (more than 6 hours). The long duration of the event may explain the deterioration in ventricular function in most cyclists in our study, as this finding coincides with the deterioration reported in studies for other longer duration tests.The decrease in LVEF in the presence of decreased systolic blood pressure reflects depressed cardiac contractility. The lack of correlation between weight changes, LVIDd and diastolic function measurements suggests that the depression in diastolic function represents a true reduction in left ventricular function. Furthermore, although post-race HR increased significantly compared to pre-race HR, the absence of any significant correlation between HR and any Doppler-derived index of diastolic function supports the presence of a change in diastolic function.Although our results agree with previously reported results, they should be interpreted with care. We report a weight loss of over 3%, which can be interpreted as a high degree of dehydration. We used weight changes and LVIDd as cardiac preload indicators; using weight loss as a preload indicator is open to question, however, as preload may be maintained by internal fluid shifts from the extravascular to intravascular space .Moreover, although LVIDd may have been used as a measure of left ventricular preload in some studies ,30,34, iAlthough our study has limitations because the parameters used to measure diastolic function are load-dependent, our findings agree with other studies that reported a reduction in diastolic function using a less load-dependent measure of diastolic function . Changes in diastolic function following exercise were unrelated to changes in preload-related indexes (LVIDd and haematocrit) and HR. Even in a controlled laboratory environment, where fluid ingestion was monitored throughout exercise and loading conditions were restored during the post-exercise assessment period, a decline in left ventricular diastolic function was observed. This suggests that the alterations in left ventricular relaxation are probably related to other underlying mechanisms .Hence, as per Shave et al. , investiThe significant increase in highly specific cardiac injury biomarkers like cTnI and NT-proBNP observed in this study indicates that myocardial damage may have occurred as a result of prolonged strenuous exercise . Damage A long-duration cycling event led to a reduction in left ventricular systolic and diastolic function in cyclists and the unrelated appearance of elevated serum markers of cardiac myocardial cell damage. Nonetheless, the mechanisms behind these outcomes remain unknown. It is likely that factors other than myocardial damage contributed to the decrease in left ventricular function after intense exercise.cTnI: Cardiac troponin I; IVSDd: Interventricular septum thickness during diastole; LVEF: Left ventricular ejection fraction; LVIDd: Left ventricular internal dimension during diastole; LVIDs: Left ventricular internal dimension during systole; LVPWd: Left ventricular posterior wall thickness during diastole; NT-proBNP: N-terminal proBNPThe authors declare that they have no competing interests.ESO conceived the study, participated in its design and coordination and helped draft the manuscript. MLR carried out tests, participated in designing the study and performed the statistical analysis. DCA carried out tests and assays and participated in designing the study. SIA helped draft the manuscript, revised it critically for intellectual content and gave final approval of the version to be published. PCE carried out the assays and participated in designing the study. CB and ALA participated in the sequence alignment and helped draft the manuscript. All authors read and approved the final manuscript.


Peripartum cardiomyopathy is a form of dilated cardiomyopathy that is defined as deterioration in cardiac function presenting typically between the last month of pregnancy and up to five months postpartum. As with other forms of dilated cardiomyopathy, PPCM involves systolic dysfunction of the heart with a decrease of the left ventricular ejection fraction with associated congestive heart failure. In heart failure sinus tachycardia is a poor prognostic factor and the common symptom. In this paper, we presented a case treated with ivabradine which provided additional benefit in patient with acute heart failure. Peripartum cardiomyopathy (PPCM) is a form of dilated cardiomyopathy that is defined as deterioration in cardiac function presenting typically between the last month of pregnancy and up to five months postpartum. As with other forms of dilated cardiomyopathy, PPCM involves systolic dysfunction of the heart with a decrease of the left ventricular ejection fraction (EF) with associated congestive heart failure. In heart failure sinus tachycardia is a poor prognostic factor and the common symptom. In this paper we presented a case, using ivabradine which provided additional benefit in patient with acute heart failure.Peripartum cardiomyopathy (PPCM) is a rarely encountered disease with high mortalities in peripartum period. The incidence of the disease differs from 1/1300 to 1/15000. Multiparity, advanced maternal age, gestational hypertension (pregnancy-induced hypertension), preeclampsia and black race are among the risk factors of the disease .If channel blocker, is a new drug for using to reduce heart rate without hemodynamic negative effect. In this paper we presented a case treated with ivabradine that provides additional benefit in patients with acute heart failure.Sinus tachycardia implicates a poor prognosis and the common symptom in heart failure. Conventional drugs such as beta blockers and calcium antagonist that used to reduce heart rate worsens the symptoms of heart failure in acute stage. Ivabradine, selective A 36-year old housewife referred to our hospital with a complaint of dyspnea starting within the 36th week of its pregnancy and continued for 2 months. Dyspnea had been significant for recent weeks even with ordinary housekeeping activities. Patient started to sleep with two pillows and according to her, the dyspnea increased while she was lying on her back. Swellings in her legs occurred and the severity of dyspnea increased gradually. The patient was referred to our hospital due to a heart failure related to pregnancy period. Patient was hospitalized in our cardiology department. In her physical examination, orthopnea and bilateral basal rales were detected. Other symptoms detected included venous distension in her neck, hepatojugular reflux, S3 (third heart sound) and pitting, ++/++ pretibial edema. Blood pressure was 105/75 and patient had a tachycardia with 119 bpm. As shown in The patient was then treated with ACE inhibitors, parenteral furosemide, spironolactone, low molecular weight heparin, digital, carnitine, oxygen and proton pump inhibitor. Since the patient’s tachycardia was associated with cardiac failure and no improvement was observed in the failure symptoms, she was administered levosimendan through the parenteral route. In her physical examination following the treatment with levosimendan, the rales in her lungs were observed to diminish, although the S3, orthopnea and tachycardia were continuing during the auscultation. On the fifth day of follow-up, metoprolol was added to the treatment of the patient with dosage of 12.5 mg per day because of ongoing resting sinus tachycardia 103 bpm, , despiteAfter including Ivabradine in the treatment, the tachycardia of the patient was ameliorated with heart rate falling to 80 bpm within 12 hours . On the Researchers showed that e heart rate is an independent indicator of mortality in heart failure . TachycaIf channel blocker, Ivabradine decreases heart rate by reducing sinus node automaticity. Researchers showed that Ivabradin decreases myocardial oxygen demand and anginal symptoms by reducing heart rate in the case of stable angina pectoris (If channel blocker with negative inotropic effect was preferred to control tachycardia.Being a selective pectoris . Besides On the third day of Ivabradine administration, patient was discharged from the hospital with a remarkable amelioration in the symptoms of congestive failure. As a result, this case showed that Ivabradine could be administered to ameliorate the symptoms and signs of heart failure in a tachycardic dilated cardiomyopathy with decompansated congestive failure. Ivabradine could be beneficial in beta blocker intolerance and tachycardic decompensated congestive heart failure.


The temporal and spatial resolution of cardiac magnetic resonance (CMR) imaging allows precise tracking of the left ventricle (LV) atrioventricular junction (AVJ) throughout the cardiac cycle. Similar to tissue Doppler imaging in echocardiography, AVJ motion assessed by CMR reflects diastolic LV function. A prior study by our group demonstrated significant differences in the displacement and velocity of the AVJ during diastole in patients with heart failure with preserved ejection fraction compared to normal hearts. In the current study we hypothesized that diastolic left ventricular function defined by AVJ motion is abnormal in patients with hypertrophic cardiomyopathy (HCM), a group known to have altered LV relaxation properties.We retrospectively identified 24 patients with known or suspected HCM and normal ejection fractions who underwent CMR as part of their clinical assessment and 14 normal control subjects. The longitudinal motion of the lateral and septal AVJs was tracked at 25 times through the cardiac cycle using the 4-chamber cine CMR view . The baseline position of the AVJ was defined at end diastole and its longitudinal displacement was measured relative to a reference line drawn between the LV apex and the midpoint of the mitral annnulus. The displacement of the AVJ in relation to its starting position at end diastole was normalized by LV length. Based on the resulting plots of AVJ position versus time in the cardiac cycle (see figure below) five motion variables were calculated: maximum longitudinal displacement (MD) of the AVJ, maximum velocity during early diastole (MVED), velocity at half-maximal displacement during early diastole (VHMDED), slope of the best fit line of displacement in diastasis (VDS), and the ratio of VDS/MVED. Data obtained in HCM patients were compared to normal control subjects using the Student t-test.Means and standard deviations were calculated for each of the AVJ motion variables  for the septal (S) and lateral walls (LW) of HCM patients and normal control subjects. Lateral and septal AVJ data were directly compared to the corresponding walls in patients and controls. We found highly statistically significant differences in MD and the four CMR correlates of diastolic LV function  in patients with HCM compared to normal controls, as noted in the table below.Novel CMR correlates of diastolic left ventricular function are markedly abnormal in patients with HCM. Measured at the AVJ, patients with HCM had significantly less maximal displacements, slower velocities during early diastolic filling, and higher velocities during diastasis compared to normal control subjects. The evaluation of AVJ motion by CMR may provide a new method to assess diastolic function.NIH 1R21HL108218-01.


In the last recent years a new percutaneous procedure, the MitraClip, has been validated for the treatment of mitral regurgitation. MitraClip procedure is a promising alternative for patients unsuitable for surgery as it reduces the risk of death related to surgery ensuring a similar result. Few data are present in literature about the variation of hemodynamic parameters and ventricular coupling after Mitraclip implantation.± 3 days after the procedure (T1), including evaluation of Ejection Fraction, mitral valve regurgitation severity and mechanism, forward Stroke Volume, left atrial volume, estimated systolic pulmonary pressure, non invasive echocardiographic estimation of single beat ventricular elastance (Es(sb)), arterial elastance (Ea) measured as systolic pressure • 0.9/ Stroke Volume, ventricular arterial coupling (Ea/Es(sb) ratio). Data were expressed as median and interquartile range. Measures obtained before and after the procedure were compared using Wilcoxon non parametric test for paired samples.Hemodynamic data of 18 patients enrolled for MitraClip procedure were retrospectively reviewed and analyzed. Echocardiographic measurements were obtained the day before the procedure (T0) and 21 Mitraclip procedure was effective in reducing regurgitation. We observed an amelioration of echocardiographic parameters with a reduction of estimated systolic pulmonary pressure  and left atrial volume . Despite a few cases decreasing in ejection fraction , the maintained ventricular arterial coupling after the procedure  was associated with an increasing in forward stroke volume .MitraClip is effective in reducing mitral valve regurgitation and determines an amelioration of hemodynamic parameters with preservation of ventricular arterial coupling. Mitral regurgitation (MR) is the second most frequent valve disease after aortic stenosis. Mitral In recent years, a new percutaneous procedure using the MitraClip® has been validated for the treatment of mitral regurgitation. The positioning of a clip approximates leaflets at different locations mimicking Alfieri’s surgical suture and creating a double orifice mitral valve. For large orifices more clips can be used to effectively reduce regurgitant volume. The EveOne of the concerns when using this procedure in patients with advanced heart failure is that the acute correction of MR could further impair LV systolic performance, leading to a low or even lower cardiac output state,8.Sunagawa demonstrated that the stroke volume produced by the heart is determined by the interaction between ventricular end-systolic elastance and arterial elastance. VentricBecause measuring Ees varying preload and ventricular end-systolic pressures invasively is difficult in clinical practice, single-beat methods were developed and validated for obtaining the Ees value (Ees(SB)). In partFor this reason, we aimed to evaluate the hemodynamic effects of the MitraClip procedure, with particular emphasis on cardiomechanics, by non invasive evaluation of ventriculo-arterial coupling.± 3 days after the procedure (T1) in all patients.After receiving approval from the ethical committee for human biomedical investigation of Azienda Ospedaliero Universitaria Pisana, a retrospective analysis of prospectively collected data from patients who had undergone the MitraClip procedure was established. Patients with high surgical risk who met the echocardiographic criteria as defined by EVEREST II were included,16. The The analysis included the following: demographic data; an evaluation of the logistic EuroSCORE; mechanism of mitral regurgitation; evaluation of mitral regurgitation severity using a multiparametric quantitative and qualitative analysis as described in Table ± SD or the median ± interquartile range. A non-parametric Wilcoxon test for paired samples was used because of the small number of patients. Results were considered significant when p < 0,05. Correlations between the Ees(SB) and the ejection fraction were evaluated using the Spearman coefficient.The data are presented as the mean ± 1 years, who were then considered in the analysis.We reviewed forty cases of the MitraClip procedure performed over two years (from June 2010 to June 2012). We found complete echocardiographic data for 18 patients  with a mean age of 73 The patients presented a logistic EuroSCORE of 30,8 ±25,2. All patients presented a diagnosis of functional MV regurgitation. The results are summarized in Table Following the MitraClip procedure, the NYHA class was significantly reduced in our patients  Figure .The main finding of this study was that the reduction of mitral regurgitation with MitraClip procedure is associated with preserved ventricular end systolic elastance (single beat) not correlated with the reduction of EF, and unchanged ventriculo-arterial coupling defined as Ea/Ees(SB) at an early follow-up.A percutaneous edge-to-edge procedure may be considered in patients with symptomatic severe MR who fulfill the echo criteria of eligibility, are judged inoperable or at high surgical risk by a ‘heart team’, and have a life expectancy greater than 1 year . The impOur study confirms the hemodynamic effects of the MitraClip procedure for patients with severe mitral regurgitation. All patients presented a significant reduction of mitral regurgitation at the time of control (T1). The reduction of MV insufficiency was associated with lowering of PAPs, left ventricular and atrial volumes and amelioration of the NYHA class status.We hypothesize that the observed reduction of the ejection fraction could not be an index of decreased systolic function, rather a consequence of a reduced preload, as evidenced by the reduction of the left atrial and ventricular volumes. Left ventricular unloading is considered one of the most important determinants of the reduction of clinical symptoms in patients after correction of mitral regurgitation by any technique (19). In the MitraClip procedure closing the MV regurgitant orifice lowers the regurgitation volume and the left ventricular and diastolic volumes during the next diastole.The analysis of ventriculo-arterial coupling in this subset of patients produced interesting results.Siegel et al. have shown that successful MV repair with the MitraClip system results in an immediate improvement in FSV, CO, and LV loading conditions and an acute reduction of the systemic vascular resistance.A post-hoc analysis has demonstrated that the hemodynamic benefit of the percutaneous procedure is higher in a particular subset of patients with a low CI and a high left-sided filling pressure and PAP.Ken-ichi Imasaka et al. demonstrated that the early surgical repair of organic mitral valve regurgitation influenced ventricular coupling in patients with preserved and impaired LV function. Measuring ventricular and arterial coupling before and 1 month after surgery, they showed that Ea increased after the procedure in all patients, but only patients with preserved function increased their contractility to rebalance ventricular coupling.Most of our patients presented impaired function with a maintained optimal Ea/Ees(SB) ratio before the procedure. We demonstrated that contractility was preserved in all patients and that Ea was not increased after the procedure. As a consequence, the lack of variation in the Ea/Ees(SB) ratio is the expression of maintained ventriculo-arterial coupling and ventricular performance after the percutaneous closure of the defect. Considering stroke volume as a function of ventriculo-arterial coupling, we can deduce that, despite reducing the EF, the combination of the restoration of normal blood ejection and the preserved Ea/Ees ratio increases the forward “effective” stroke volume after the MitraClip procedure.Our findings are supported by the recently published data by Gaemperli et al. who investigated the acute behavior of pressure volume relationships in patients undergoing Mitraclip procedure. Based on the invasive measurements obtained with conductance catheters during the intervention they found no acute variations of PV loop area and increased CI following MV repair.Our study shows limitations due to its retrospective design and the small number of patients analyzed. Our results have been obtained in a non-invasive manner and we cannot exclude differences if data were obtained invasively monitoring ventricular and vascular load determinants, although recent evidence seems to support our results. HoweverWritten informed consent was obtained from the patients for publication of this report and any accompanying images.Key message:• MitraClip is an effective procedure in reducing mitral valve regurgitation in high surgical risk patients.• MitraClip procedure has favorable hemodynamic impact. The reduction of Mitral regurgitation is associated with preserved Ea/Ees(sb) ratio and increased forward stroke volume.• Non invasive evaluation of cardiomechanics is feasible and may be useful in patients undergoing MitraClip procedure.None of the authors have any financial competing interests.FG: participated in the design of the study, wrote and reviewed the manuscript. FB: collected data, wrote and reviewed the manuscript. BR: collected data and reviewed the manuscript. BP: has been involved in drafting the manuscript and revising it critically for important intellectual content. GC: collected data and reviewed the manuscript. DBV: has been involved in critically revising the final manuscript. PAS: has been involved in drafting the manuscript and revising it critically for important intellectual content. All authors approved the final version of manuscript.


Delayed enhancement (DE) CMR is the gold standard for detecting irreversibly damaged myocardial tissue (scar) . Yet, direct impact of scar on regional systolic and diastolic left ventricular (LV) function is not well understood. Standard tools for LV velocities (Tissue Doppler Imaging) are limited by poor reproducibility and incomplete assessment of all regions and motion directions. Myocardial CMR velocity mapping (MVM) is reproducible, non-invasive, and allows direct measure of myocardial velocities of all LV motion components in all regions. Here, we analyze effects of LV scar burden on myocardial motion.CMR  with DE-CMR (inversion recovery PSIR) and MVM in 49 patients (age=54±16 years) with cardiomyopathy (n=16), normal myocardium (n=10), inflammatory disease (n=4) ischemic heart disease (n=3), heart failure (n=3), and other (n=13) were acquired in basal, mid-ventricular, and apical short axis orientation during breath hold. DE-CMR: A radiologist assessed whether scar was present in segments from the AHA 16-segment model and classified based on number of segments with scar . MVM: Consisted of black-blood prepared CINE phase-contrast sequence with 3-directional velocity encoding . Data analysis included manual segmentation of LV contours and conversion of measured velocities into radial, rotational, and long-axis velocities. Systolic and diastolic radial and long-axis velocities were derived and mapped on the AHA 16-segment model. Global  radial and long-axis velocities were analyzed using t-test.Patients with high scar showed reduced regional peak velocities compared to patients with no and low scar figure . SystoliDE-CMR and MVM, measuring scar burden and regional myocardial velocities, were co-registered to detect impaired regional myocardial structure and function. Segmental analysis showed significant decreases in mean velocities in patients with high scar indicating a direct relationship between structural damage to the LV and impaired myocardial function. Future work will analyze specific patient groups and assess other changes in velocity markers.AHA 12GRNT 12080032


Repaired tetralogy of Fallot (rtoF) patients are at risk ventricular tachyarrhythmia and sudden cardiac death. Risk stratification for arrhythmia remains difficult.We aimed to investigate whether cardiac anatomy and function assessed by cardiac magnetic resonance imaging (CMR) predict arrhythmia.One-hundred-and-fifty-four adults with rtoF, median age 30.8 (21.9-40.2) years, were studied with a standardised protocol including cardiovascular magnetic resonance (CMR) and prospectively followed-up over median 5.6 (4.6-7.0) years for the pre-specified endpoints of new-onset ventricular tachyarrhythmia (sustained ventricular tachycardia/ventricular fibrillation).Nine patients had ventricular tachyarrhythmia (6%) during follow-up. Patients who developed ventricular tachyarrhythmia were older , had a later repair , larger akinetic right ventricular outflow track (RVOT) region   and a lower RV ejection fraction , compared to the other patients. On univariate Cox analysis, RVOT akinetic region length and RV ejection fraction were predictive of ventricular tachyarrhythmia. On stepwise Cox regression analysis, the RVOT akinetic region length was the only remaining predictor . The survival ROC curve analysis indicated a cut-off value of 30mm as a predictor of VA during 6 year follow-up with an AUC of 0.77, sensitivity of 83% and specificity of 61%. RVOT akinetic area length >30mm predicted reduced VA-free survival (Logrank p=0.002).Conclusions: RVOT akinetic region length predicts ventricular arrhythmia in late follow-up of rtoF. This is simple, feasible measurements for inclusion in serial surveillance and risk stratification of rtoF patients.British Heart Foundation Fellowship (SVB-N).French Federation of Cardiology (BB).Unrestricted Actelion educational grant (GD).The study was supported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.


Although dabigatran, a novel oral anti-coagulant, has been approved for the prevention of thromboembolism in patients with non-valvular atrial fibrillation, the efficacy of dabigatran for the resolution of established intra-cardiac thrombi has not been validated. Herein is describe a case in which dabigatran was effective for thrombus resolution in a patient with a left ventricular aneurysm.A 59-year-old Japanese man with a mid-ventricular obstructive hypertrophic cardiomyopathy-associated apical aneurysm presented with a left ventricular apical thrombus (15.0mm×17.0mm). Anti-coagulation therapy with dabigatran  was initiated. Following dabigatran administration, weekly echocardiographic examinations demonstrated gradual decreases in thrombus size. After three weeks, no thrombus was detected and no systemic thromboembolic events had occurred.The left ventricular apical thrombus resolved after dabigatran administration. Hence, dabigatran may represent an alternative to warfarin as a therapeutic option in patients with previously detected intra-cardiac thrombus. In general, heparin and warfarin are used for the treatment of intra-cardiac thrombi. Dabigatran is a novel oral anti-coagulant that has recently been approved for use in the prevention of thromboembolism in patients with non-valvular atrial fibrillation. However, because of limited dabigatran use in such situations, there are relatively few reports in the literature regarding the efficacy of dabigatran for the resolution of established intra-cardiac thrombi. Herein described is the effectiveness of dabigatran for thrombus resolution in a patient with a left ventricular aneurysm.A 59-year-old Japanese man presented for treatment of an intra-cardiac thrombus. At 52 years of age, he was diagnosed with mid-ventricular obstructive hypertrophic cardiomyopathy (HCM) associated with paroxysmal atrial fibrillation. Electrocardiography revealed poor R-wave progression at the V4 and V5 leads, and echocardiographic images demonstrated asymmetrical septal hypertrophy and mid-ventricular obstruction associated with paradoxical diastolic flow Figure . Althouget al. reported the clinical courses of 28 patients with HCM-associated apical aneurysms over a mean follow-up period of 4.1±3.7 years, in which embolic stroke or left ventricular apical thrombus was detected in four patients [Mid-ventricular obstructive hypertrophic cardiomyopathy is a rare form of HCM, accounting for approximately 5% of all HCM cases . HoweverDabigatran is a reversible direct thrombin inhibitor which has been approved for the prevention of thromboembolism in patients with non-valvular atrial fibrillation  and in tet al. [In contrast, the efficacy of the oral anti-coagulant dabigatran in the resolution of previously detected thrombus has not been extensively reported. Vidal et al.  reportedet al. , which aBecause thrombus resolution was successful in the present case, dabigatran may have the potential to be used as an alternative to warfarin in patients with established intra-cardiac thrombus. However, additional cases are needed to determine if dabigatran is effective for the resolution of intra-cardiac thrombus.Written informed consent was obtained from the patient 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.PT-INR: Prothrombin time internationalized ratio; TAT: Thrombin-anti-thrombin III complex.The author declares that he has no competing interests.BK analyzed and interpreted the patient data and wrote the manuscript.


Spin echo Axial T1 images are used to evaluate the great vessels and cardiac structures. In some patients with depressed left ventricular ejection fraction (LVEF) the sequence fails to null blood of the descending aorta (dAo) at the level of the main pulmonary artery (MPA). This may represent stasis of blood from the aorta and reflect a decreased LVEF, stroke volume (LVSV) and/or cardiac output (CO). This finding has not systematically been studied. We evaluated the relationship between opacification of the descending aorta and cardiac functional parameters.148 consecutive cardiac MR scans performed between 7/2010 and 9/2010 that included evaluation of left ventricular function were reviewed. The T1 axial images (SE-EPI TR750TE20Flip90) were evaluated for opacification of some or all of the dAo at the level of the MPA. This was also identified in either the slice above or below this level to be considered a positive finding. The values of LVEF, SV, and CO as determined by manual tracings and application of Simpson’s rule were obtained .Mean LVEF value for patients with no opacification was 60% while those with any amount of opacification had a mean LVEF of 36% (p < .0001). Specificity and sensitivity for LVEF < 55 was 97% and 32% respectively, for LVEF < 45 was 95% and 40% respectively, and for LVEF < 35 was 93% and 53% respectively. The mean SV value for patients with no opacification was 96 ml while those with any amount of opacification had a mean LVSV of 58 ml (p < .0001). Specificity and sensitivity for LVSV < 50 ml was 92% and 53% respectively. The mean CO value for patients with no opacification was 6.2 L/min while those with any amount of opacification had a mean CO of 4.5 L/min (p < .0001). Specificity and sensitivity for CO < 5.0 L/min was 96% and 38% respectively.Opacification of the descending aorta at the level of the MPA is a specific but not sensitive finding for depressed LVEF and lower than normal LVSV and CO. When this finding is observed, further evaluation of a patient’s ejection fraction should be considered.


CRT is an effective treatment for patients with heart failure and intraventricular conduction delay. However, clinical non-response rates remain unacceptably high; emphasizing the need for improved selection criteria. Central to the underlying mechanism of resynchronization is the relationship between mechanical and electrical activation. The purpose of this study was to demonstrate that mechanical and electrical activation can be quantified in patients with CRT devices combining cardiovascular magnetic resonance (CMR) and electrical myocardial imaging (EMI).Non-invasively characterize mechanical and electrical activation patterns in patients undergoing cardiac resynchronization therapy (CRT)Patients implanted with biventricular CRT for greater than 9 months (N=10) were mapped with 120 body surface electrodes during both intrinsic activation (device off) and CRT pacing. CMR tagging was also acquired with pacing on/off to perform strain analysis. The circumferential uniformity ratio (CURE) was computed to characterize temporal-spatial mechanical dyssynchrony . CMR images of the torso and heart were then used to reconstruct electrical epicardial activation maps using a novel EMI technique. Electrical synchrony was indexed by the mean total activation difference time . Only 2 patients underwent full analysis.CURE decreased from 0.73 to 0.51 when the device was turned off, indicating an increase in mechanical dyssynchrony. The corresponding LVEF decreased as well in on/off modes from 42% to 29%. Figure CMR and non-invasive EMI are feasible in patients with CRT devices. This ability to quantify mechanical and electrical synchrony before and after CRT may provide insights into mechanisms of resynchronization and lead to robust dyssynchrony metrics that will identify appropriate candidates for CRT.


Right ventricular dysfunction represents a common problem in patients with congenital heart defects, such as Tetralogy of Fallot or pulmonary arterial hypertension. Patients with congenital heart defects may present with a pressure or volume overloaded right ventricle (RV) in a bi-ventricular heart or in a single ventricular circulation in which the RV serves as systemic ventricle. Both subsets of patients are at risk of developing right ventricular failure. Obtaining functional and morphological imaging data of the right heart is technically more difficult than imaging of the left ventricle. In contrast to findings on mechanisms of left ventricular dysfunction, very little is known about the pathophysiologic alterations of the right heart. The two main causes of right ventricular dysfunction are pressure and/or volume overload of the RV. Until now, there are no appropriate models available analyzing the effects of pressure and/or volume overload on the RV. This review intends to summarize clinical aspects mainly focusing on the current research in this field. In future, there will be increasing attention to individual care of patients with right heart diseases. Hence, further investigations are essential for understanding the right ventricular pathobiology. In patients with congenital heart disease (CHD), the right ventricle (RV) serves in a bi-ventricular heart as subpulmonal ventricle or in a single ventricular circulation as the systemic ventricle. RV dysfunction is a common problem in the clinical care for patients with CHD. Clinical relevance for research projects in the field of RV dysfunction is given by the following examples:Tetralogy of Fallot after intracardiac repair: Volume overload of the RV due to pulmonary regurgitation results in RV dilatation and RV dysfunction. Significant RV dilatation with an end-diastolic volume >170 ml/m2 or an endsystolic volume >85 ml/m2 is associated with persistent RV dilatation even after successful surgical pulmonary valve replacement by using a valved homograft (Univentricular heart with RV predominance: Morphology and function of the systemic ventricle (right versus left) are important factors influencing the long-term prognosis after Fontan type  repair. Precisely, RV morphology of the systemic ventricle is associated with a much worse outcome and RV dysfunction is associated with higher mortality and morbidity rates in this group of patients . Long persisting RV outflow tract obstruction (RVOTO) will finally lead to systolic and diastolic RV dysfunction.d-transposition of the great arteries (d-TGA) the RV serves as the systemic ventricle. The survival rate of these patients has been reported with 76% at 20 years of age, the mean age at death was 27 years (ccTGA). In both conditions, adolescents and young adults are prone to RV failure which finally necessitates orthotopic heart transplantation  has been shown to improve mortality and morbidity in adult patients with refractory heart failure and prolonged QRS duration. In children and CHD patients treated with CRT heart failure symptoms have been found to improve at a mean follow-up of 0.7 years . HoweverCurrently, stem cell therapy with cardiac progenitor cells (CPCs) is under evaluation in clinical trials . Rupp anTaking these features and the consequences for lifelong care for these patients into account, there is a need to initiate research projects addressing the pathophysiology of the RV under the conditions of pressure and/or volume overload.2 (by MRI or multi-detector computed tomography imaging) and data from exercise tests (peak exercise systolic blood pressure below 180 mmHg) was found to identify patients with a 20-fold higher annual event rate compared to patients without these risk factors  has gained wide acceptance to evaluate RV morphology and function. Imaging of the RV nowadays aims at giving prognostic information for patients with RV volume and/or pressure overload. In patients with a systemic RV, the combination of a RV end-diastolic volume index above 150 ml/mThe right and left ventricle strongly interact. Therefore it is impossible to view abnormalities of the RV without taking the left ventricle into account , what haIn Tetralogy of Fallot, MRI is the gold standard for lifetime imaging Figure A. EchocaThe RV performance can be reproducibly assessed in patients with Tetralogy of Fallot by measuring the tricuspid annular plane systolic excursion (TAPSE). The correlation of TAPSE with right ventricular ejection fraction (RVEF) is a matter of debate: whereas some groups report a correlation between TAPSE and RVEF in patients with pulmonary arterial hypertension (PAH) associated with CHD , other g®, is needed to obtain these data by echocardiography  which limit the surgical techniques available for palliating the situation. In order to answer the question regarding “the best potential repair” in patients with Fallot tetralogy and hypoplastic pulmonary valve and arteries, a large prospective collaborative investigation would be necessary aiming at acquiring follow-up data extending over several decades  recently failed to offer a true advantage and showed a high failure rate . Future The correction of residual anatomic defects  earlier in life seems appropriate given the pathophysiology of RV deterioration in these patients. However, data are lacking evaluating a more conservative and observant regimen until conduit placement versus a concept with earlier surgical intervention.Acute RV failure is a major risk factor for mortality of patients after orthotopic heart transplantation when pulmonary vascular disease is present such as in chronic left heart failure. An early mortality rate of 19% has been reported in this subset of patients . ReportsThere are new surgical techniques on the horizon aiming at improving RV systolic function in patients with dilated RV after surgery for CHD. Tang and coworkers have recently published a mathematical model analyzing the effects of placing an elastic band in the RV on RVEF . TherefoResearch focusing on RV dysfunction – especially in the context of congenital heart defects – is urgently required. We need to better understand the underlying pathophysiological mechanisms of RV dysfunction in patients with CHD. Even though the RV, when compared to the left ventricle, differs on a morphological, physiological, and molecular level, the RV has gained in scientific interest in the last few years. Extensive work has just begun in order to unravel the etiology of RV dysfunction.The morphology of the RV, which has a thinner wall than the left ventricle, enables a quick adaptation to changes in preload under physiological conditions. An important mechanism of adaptation of the RV to high pressure is to increase wall thickness by accumulating muscle mass (hypertrophy) and to assume a more rounded shape . The celThe hypertrophic response of cardiomyocytes to pathological conditions leads to changes at the transcriptional level such as an increase of protein synthesis and alterations of fetal genes. Typical markers for fetal gene expression that are merely expressed in fetal ventricles are atrial and brain natriuretic peptides, skeletal α-actin or β-myosin heavy chain . It was The ECM is an essential part of the matrix scaffold of the heart and consists predominantly of collagen with relatively small amounts of fibronectin, laminin, and elastin. The close proximity of the contractile apparatus implies that the ECM influences the systolic and diastolic function as well as ventricular size and shape , 51. IncAngiotensin II (Ang II), Endothelin-1 (ET-1), and other neurohormones are able to induce hypertrophic pathways within the cardiomyocyte, in part, by formation of reactive oxygen species (ROS) . In leftNeutrophils may be an important source of excessive ROS formation in heart failure. In parallel with the recruitment of immune cells, proinflammatory cytokines play a complex role in the development of heart failure. Hemodynamic and clinical parameters of disease severity correlate with increased serum levels and expression of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 by cardiomyocytes . Recent In conditions with increased afterload  the systolic right coronary artery flow is reduced as assessed by MRI . There i4 to 105 cells)  , it has 5 cells) . In the 5 cells) . In the 5 cells) . There i5 cells) , 69, butNotable analyses of gene expression patterns and epigenetic modifications during maladaptive processes in the heart revealed differences between the left and RV , 71. ThuCongenital heart defects and other diseases associated with RV impairment show a wide variety of causes Figure . Many geUntil now, there is merely one study known about volume overload of the RV in a small animal model, possibly due to technical difficulties in implementation. Reddy and colleagues generated the first murine model for pulmonary insufficiency and analyzed its physiologic and molecular characteristics. In their model, RV volume overload resulted in declined heart function and altered expression of various genes that are involved in mitochondrial and G protein-coupled receptor signaling . In contBesides the great advantage of large animal models because of their better comparability to human disease settings and easier implementation of operation techniques, large animals produce high costs and are more laborious in keeping. One of the most important strategies to uncover the etiology of diseases associated with the right heart will be the use of genetic approaches and small animal models. Even conspicuous is the predominant utilization of rodent animal models such as mice and rats based on their many advantages like the presence of a four chambered heart and an extensive knowledge of their genetics . The mosCurrent efforts in studying RV pathomechanisms in the setting of experimental PAH generated new interesting findings. Sutendra and colleagues could show that in monocrotaline treated rats the earlier described metabolic shift is not sustained during the development of RV failure . FurtherAll these models, however, could not reflect the real clinical presentation of patients with RV dysfunction. The strengths and weaknesses of various animal models emphasize the urgent need for better models to uncover the disease mechanisms in the RV. Mice overexpressing signaling components such as serotonin transporter (SERT), bone morphogenetic protein receptor-2 (BMPR-2), or S100A4 that are involved in right heart failure could only demonstrate details of maladaptive processes in the right heart. More detailed analyses such as investigations in the RV specific ubiquitin-proteasome signaling  or analyIn the future, RV dysfunction will represent a growing problem due to the increasing number of patients with CHD surviving into adulthood with the morphological RV serving as the systemic ventricle. In addition, patients after pulmonary artery conduit implantation are at risk for developing RV dysfunction due to volume or/and pressure overload during their whole lifetime.At present, most knowledge of RV dysfunction is mainly derived from diseases of the left ventricle. Experimental work has to be performed to obtain more insight into the pathophysiology of RV dysfunction. Modern imaging techniques such as molecular imaging may give more information on the myocardial metabolism during RV dysfunction. Current pharmacological treatment is based on a small panel of drugs, which exert no right heart specific properties. Therefore, future research has to be focused on developing a targeted drug therapy for these patients.We expect major improvements in the therapy of RV dysfunction by technologies that will enable the placement of smaller ventricular assist devices in patients presenting with acute and chronic right heart failure. Stem cell therapy is another promising therapeutic approach worth mentioning.However, the knowledge gained by translational and molecular biological research will lead to a more targeted therapy for treating the failing RV.Matthias Gorenflo was responsible for the concept of this manuscript and contributed to major parts of the manuscript. Raoul Arnold contributed to the imaging section. Tsvetomir Loukanov contributed to the section on surgical therapy. Doreen Köhler was responsible for the experimental section of this manuscript and for editing the manuscript.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.


Indeed, major randomized clinical trials suggest that suboptimal use of fundamental drugs, such as ACE inhibitors (ACE-i) and beta-blockers, may affect ICD shock-free survival, sudden cardiac death (SCD), and overall mortality. While solid evidence in favour of pharmacological therapy based on ACE-i with or without beta-blockers is available, data on SCD in HF patients treated with angiotensin receptor blockers (ARBs) are limited. The present paper systematically analyses the impact of ARBs on SCD in HF and reviews the contributory role of the renin-angiotensin system (RAS) to the establishment of arrhythmic substrates. The following hypothesis is supported: (1) the RAS is a critical component of the electrical remodelling of the failing myocardium, (2) RAS blockade reduces the risk of SCD, and (3) ARBs represent a powerful tool to improve overall survival and possibly reduce the risk of SCD provided that high doses are employed to achieve optimal AT Heart failure (HF) affects 15 million people in Europe, with a prevalence of 2-3% in the general population and 10–20% in 70- to 80-year-old subjects. It represents the common ending of different cardiovascular diseases and is characterized by high short-term mortality in advanced stages (up to 50% at 1 year for NYHA class IV patients) .β-blockers and ACE inhibitors [Death in HF occurs either from circulatory failure due to progressive left ventricular (LV) dysfunction or sudden cardiac death (SCD). This latter accounts for approximately half of all HF deaths, the underlying mechanism being sudden onset of ventricular tachycardia (VT) or ventricular fibrillation (VF). Despite decades of research for the evaluation of hundred compounds, there are no antiarrhythmic drugs that definitely prevent SCD in HF patients on already optimized therapy with hibitors . In conthibitors –8.β-blockers and ACE-inhibitors among the study arms [β-blockers, and less than 70% of patients were treated with ACE-i. While solid evidence in favour of pharmacological therapy based on ACE-i with or without beta-blockers is available, data on SCD in HF patients treated with ARBs are limited.Based on data from multiple randomized primary prevention trials, current guidelines recommend ICD implantation in patients with symptomatic and severe LV dysfunction of any origin on already optimized medical therapy . Howeverudy arms . Findingudy arms , DINAMITudy arms , DEFINITudy arms , and MADudy arms  trials, The present paper systematically analyses the impact of ARBs on SCD in HF and reviews the contributory role of the renin-angiotensin system (RAS) to the establishment of proarrhythmic substrates.P = 0.08) [The ELITE study  was orig = 0.08) .P = 0.0007) as compared to placebo. In addition, resuscitation of cardiac arrest was improved with valsartan, without achieving statistically significance . However, at the time of randomization, about 93% of patients were on ACE inhibitors in both treatment arms, not allowing to assess the isolated benefits of ARBs.The Val-HeFT trial  Table 1Table 1 wP = 0.07) and SCD  in the losartan as compared to captopril group.In the OPTIMAAL trial  Table 1Table 1, n = 903) or resuscitated cardiac arrest (n = 164) in a median of 180 days after MI. The risk was the highest in the first 30 days after MI (1.4% per month) and was decreased (0.14% per month) after 2 years. Unfortunately, this analysis did not address which of the drug regimens was more effective in preventing SD or resuscitated cardiac arrest.The VALIANT study  Table 1Table 1 rThe CHARM programme , includiThe low doses of ARBs used in the former trials may at least in part explain the higher mortality as compared to that observed in the CHARM overall programme. This hypothesis is also supported by the recent findings of a registry-based cohort study  assessinAll these studies suggest that undertitration of ARBs may be associated with a poor outcome. Less information is given if beta-blocker cotreatment influences the dose response of ARBs. Of note, patients enrolled in all the above-mentioned trials were on optimized medical treatment including beta-blockers, the only drugs that proved to be effective in reducing sudden cardiac death, cardiovascular death and all cause mortality in HF . In VALIAmong clinical trials that demonstrated a significant survival benefit of the ICD , 8, 25, In a post hoc analysis of the COMPANION trial , Saxon eIn a population of ICD recipients with left ventricular ejection fraction <35% and no prior documented ventricular arrhythmias, Obeyesekere et al.  Table 1Table 1 r1-subtype receptor  are higher than those commonly used in clinical practice. In their experience on normotensive healthy volunteers, Mazzolai et al. [1 receptors. This is consistent with findings from Maillard et al. [1 receptor blockade. In their study, oral administration of losartan 50 mg induced only 50% AT1 receptor blockade, which was comparable to valsartan 80 mg. Blockade of 67% of AT1 receptors required valsartan 160 mg.Based on the pharmacodynamic profile of ARBs, dosages required to achieve a complete blockade of the ATi et al.  found thd et al. , who repP = 0.025) and showed a nonsignificant trend towards reduction in mortality  as compared with losartan 50 mg/day. Among components of primary endpoint, SCD and progressive HF represented the most common causes of death .Notably, main trials in HF patients allowed ARB doses that are considerably higher than those traditionally employed in clinical practice. In the Val-HeFT  the targmilieu for triggering and propagation of ventricular arrhythmias. Local RAS expression contributes substantially to myocardial structural changes that favour cardiac arrhythmias [1 receptor. Among AT1 receptor-mediated mechanisms, angiotensin II decreases gap junction conductance via protein kinase C activation [2+-ATPase pump and ryanodine receptor [2+ leak and defective SR Ca2+ reuptake during diastole. The resultant cytoplasmic Ca2+ overload can trigger delayed afterdepolarizations and ventricular arrhythmias [1 receptors are widely expressed in the cardiac conduction system, angiotensin II may promote electrical instability also via enhanced spontaneous activity trough activation of the AT1 receptor in the sinoatrial/atrioventricular node and Purkinje fibres. Indeed, in isolated cardiac Purkinje fibres, angiotensin II increases the height and duration of the plateau phase of the action potential and promotes an inward shift in membrane current [Myocardial remodelling of the failing heart involves progressive loss of tissue due to necrosis and fibrosis, leading to inhomogeneous electrical conduction and offering the ideal hythmias . Angiotetivation , shortentivation , and modtivation . Indeed,receptor , 38, thuhythmias , 40  reduces scar size by diminishing Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect [It is noteworthy that the contributory role of ATtor mRNA . Moreovec effect . It seem1 receptors. As compared to ACE-i, ARBs have the advantage to inhibit the production of angiotensin II via ACE-independent pathways, providing a long-lasting effect that overwhelms possible loss of efficacy of ACE-i after prolonged use. Furthermore, ACE-i may increase bradykinin levels, which in turn trigger norepinephrine release leading to higher susceptibility to cardiac arrhythmias. Conversely, ARBs do not hydrolize ACE, thus preventing bradykinin increase.Both ACE-i and ARBs counteract the proarrhythmic effects of angiotensin II. Indeed, ACE-i prevent the conversion of angiotensin I to angiotensin II, while ARBs directly block AT1 receptor pathways. In the clinical arena, drug treatment with ARBs represents a powerful tool to reduce the risk of cardiac arrhythmias, provided that full drug doses are employed. Indeed, randomized controlled trials showed that high doses of ARBs  are effective in improving survival in HF and may be therefore warranted also to reduce the risk of SD. On the contrary, using ARBs in this setting at suboptimal doses provides less than optimal receptor blockade, which turns to be clinically inadequate in severely diseased patients. In this view, the efficacy of high-dose ARBs in protecting HF patients from life-threatening arrhythmias should be prospectively assessed.The RAS contributes substantially to myocardial electrical remodelling of the failing heart, favouring ventricular arrhythmias. In experimental settings, RAS blockade through ACE-i and ARBs , 47, 50


Reperfusion into severely ischemic myocardium can lead to myocardial hemorrhage (MH). Recent studies have employed T2- and T2*-weighted imaging to assess MH. However, a direct comparison of myocardial T2 and T2* changes in the setting of MH is not available.To examine the T2 and T2* changes associated with MH and thereby determine the effectiveness of each method for detecting MH.Canines (n = 9) were subjected to a 3-hour occlusion of the LAD followed by reperfusion. Serial CMR studies (1.5T Siemens Espree) were performed post-reperfusion on days 2, 5 and 7. Short-axis images of the entire LV (resolution = 1.1x1.1x8mm3) were obtained using T2-prepared SSFP , multi gradient-echo  and PSIR Late-Enhancement (LE-PSIR) imaging. T2 and T2* maps were computed from T2-prepared and gradient-echo acquisitions. Hemorrhagic infarctions (MH+) were determined by the presence of hypointense territories on T2* maps within the infarcted zones identified from LE-PSIR images. In the MH+ group, manually drawn ROIs on the T2* maps around the hemorrhagic cores and remote territories were copied to the T2 maps. In non-hemorrhagic infarctions (MH-), manually drawn ROIs on LE-PSIR images around the infarcted zones and remote territories were copied to T2 and T2* maps. T2 and T2* values from the MH+, MH- and remote territories were measured and compared (p<0.05).MH was observed in 6 dogs (MH+), but not in the remaining 3 dogs (MH-). Figure T2* of MH+ territories were significantly lower than those of MH- and remote territories. This was not the case amongst T2 of MH+, MH- and remote territories. The reduced conspicuity of MH on T2 maps is likely due to the refocusing effects of the 180o pulses and its intrinsic sensitivity to myocardial edema. We conclude that the potential insensitivity of T2*-weighted CMR to myocardial edema and strong sensitivity to hemorrhagic byproducts makes T2* mapping a more effective approach for detecting MH.