Whole Body Periodic Acceleration (pGz) is a non-invasive technology that increases pulsatile shear stress to the endothelium thereby producing several beneficial cardiovascular effects as demonstrated in animal models, normal humans and patients with heart disease. pGz upregulates endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS) to improve myocardial function in models of myocardial stunning and preconditioning. Here we test whether pGz applied chronically after focal myocardial infarction in rats improves functional outcomes from MI. Focal MI was produced by left coronary artery ligation. One day after ligation animals were randomized to receive daily treatments of pGz for four weeks (MI-pGz) or serve as controls (MI-CONT), with an additional group as non-infarction controls (Sham). Echocardiograms and invasive pressure volume loop analysis were carried out. Infarct transmurality, myocardial fibrosis, and markers of inflammatory and anti-inflammatory cytokines were determined along with protein analysis of eNOS, p-eNOS and inducible nitric oxide synthase (iNOS).At four weeks, survival was 80% in MI-pGz vs 50% in MI-CONT (p< 0.01). Ejection fraction and fractional shortening and invasive pressure volume relation indices of afterload and contractility were significantly better in MI-pGz. The latter where associated with decreased infarct transmurality and decreased fibrosis along with increased eNOS, p-eNOS. Additionally, MI-pGz had significantly lower levels of iNOS, inflammatory cytokines , and higher level of anti-inflammatory cytokine (IL-10). pGz improved survival and contractile performance, associated with improved myocardial remodeling. pGz may serve as a simple, safe, non-invasive therapeutic modality to improve myocardial function after MI.Myocardial infarction (MI) may produce significant inflammatory changes and adverse ventricular remodeling leading to heart failure and premature death. Pharmacologic, stem cell transplantation, and exercise have not halted the inexorable rise in the prevalence and great economic costs of heart failure despite extensive investigations of such treatments. New therapeutic modalities are needed.  Myocardial Infarction (MI) and its associated functional derangements may lead to heart failure that affects 2–3% of the population in industrialized countries with a marked rise in those aged >65yr. A combined estimate of ~ 20 million people suffer from heart failure in Europe and the US and its prevalence is increasing. In the US alone direct medical costs approximate $25 billion dollars per year and expected to triple by 2030 –4.(Ser 1177)  immediately after surgery and every 6 to 12 hr. based on pain assessment. Animals are monitored hourly or until upright and ambulating. Once ambulating animals are assessed for post procedural pain every 4 hr. for the initial 48 hr., thereafter once per day until completion of the protocol. A modified score sheet system based on post procedural pain assessment of behavior, physiological stress signs and respirations is used to tabulate assessments  intubated and ventilated with Oessments  15–17].–17.2 usiEchocardiograms where performed post MI at 1, 3,and 4 weeks of pGz or Control using an HP Sonos 2000 ultrasound imaging system  with a 7.5 mHz transthoracic transducer. 2D/M-Mode techniques were applied to assess functional changes. Echocardiograms were performed in long- and short-axis following myocardial infarction in close-chest sedated rats. The chest was shaved and covered with ultra sound gel in order to provide air-free insonation. The left ventricle (LV) was visualized by middle long and short axis images. Middle long and short axis views were taken from the right ventricular side in order to depict the left ventricle at a lower sector-angle. By reducing insonation angle without reducing spatial resolution, the technique provided images with a 76 frame rate. Three cardiac cycles were acquired and averaged by software. The correct tracking of border zones was visually controlled and manually corrected. Ejection time was defined by Doppler-registered aortic valve opening and closure. Conventional measurements  and posterior wall (PW) thickness and thickening) were obtained from grayscale M-mode tracings. LV end-systolic and end-diastolic volumes and LV ejection fraction (LVEF) were measured by Simpson’s method from two-dimensional parasternal long- and short-axis views –20.After four weeks of pGz or Control the animals where anesthetized and catheterization was performed with a Millar Catheter SPR-869 . The conductance catheter was calibrated by a cuvette calibration method using an actual blood sample in cuvette between 50 and 300 μl. In vivo the conductance signal was calibrated using hypertonic saline. An intravenous bolus of 50 μl of 20% saline was used to perform calibration. In order to decrease preload, a small abdominal incision was performed to localize and perform inferior vena cava (IVC) occlusions. PVL where continuously recorded at baseline, after saline infusion, and during and after IVC occlusions. Recording and calculations were performed using data acquisition software .Sham protocol was identical to MI experiments with the exception of coronary artery ligation. At the completion of the sham surgery, animals were recovered and allowed to remain in their cage with free access to chow and water for the remainder of their study time period.Animals which met pre-established humane endpoints for euthanasia or completed the experimental protocol were euthanized by a dose of Ketamine 90mg/kg and Xylazine 25mg/kg, followed by pentobarbital 100mg/kg IP, until absence of corneal and pedal reflex, and no electrical activity on ECG, and decapitation via guillotine, a method approved by the American Veterinary Medical Association Guidelines on Euthanasia. Perfusion and or organ harvesting was performed as per protocol –24.Validation of coronary occlusion was performed by our laboratory according to the procedure previously described . In a seArea at risk measured by the Evans Blue (EB) perfusion-staining and expressed as percent of whole heart. Necrosis was measured by TTC staining and expressed as percent of each myocardial segment. To determine transmurality of the infarct scanned images of the segments were geometrically divided into a 6-sector model using the anterior and inferior insertion of the right ventricle to the left ventricle as markers . Apical,Transmural necrotic sectors display thinning of the myocardial circumferential areas of left ventricular wall. Transmurality of the infarct was defined as the sum of the epicardial and endocardial infarct circumference divided by the sum of the total LV epicardial and endocardial circumferences using computer-based planimetry . Fibrosi(Ser1177) iNOS, and GADPH  as an individual protein loading control  were employed. TNF-α, IL-6, IL-10 where determined using Rat Cytokine Kit . Equal amounts of protein 400 μg were used for analysis. Cytokine levels where normalized to Sham samples. Blots were visualized by Enhanced Chemifluorescence (ECF)  on Storm 860 Imaging System . The Storm 860 Imaging System exhibits a linear response to fluorescent signal intensities and protein levels were quantified using ImageQuant software .To assess the effects of pGz on eNOS, p-eNOS and iNOS and inflammatory TNF-α, IL-6 and anti-inflammatory cytokine IL-10 protein levels were determined. Samples of the left ventricle were removed and immediately frozen in liquid nitrogen for Western Blot and cytokine protein chemiluminescent analysis. Care was taken to consistently harvest the same region of the left ventricle from all animals. Sections of the left ventricular myocardium were individually minced and homogenized at 4° C followed by one step total protein extraction with an Extraction Buffer System  according to the manufacturer’s protocol. Homogenates were centrifuged at 4°C for 20 minutes at 12,000 rpm. The supernatant was decanted and assayed for total protein content. The extracted total cardiac tissue protein was measured by the BCA Protein Assay  on a SpectraMax Plate Reader . Individual proteins were then analyzed by Western Blot. Equal amounts of total protein were separated on 4–12% NuPAGE Novex Bis-Tris SDS-PAGE Gels  and transferred to Immobilon-FL PVDF membrane . The PVDF membrane was treated with a blocking agent  and probed with primary, fluorescein-linked secondary antibodies as well as anti-fluorescein alkaline phosphatase conjugate. Primary antibodies to eNOS, p-eNOSpost hoc. Statistical significance was established at p<0.05. Sample size was calculated using Statistica  based on power analysis with α = 0.05 and power 0.80. All data are expressed as Mean ± SD.Primary outcomes are survival and myocardial infarct size. Secondary outcomes are myocardial fibrosis, hemodynamics and protein expression. Myocardial contractility measurements were analyzed using a two-way analysis of variance with repeated measures. When appropriate, post hoc Fisher’s least significant difference test was carried out. Myocardial protein analysis parameters were subjected to analysis of variance with a Fisher’s least significant difference test used All animals survived myocardial infarction without reperfusion at 24 hr. At 1 week post MI, 70% of the MI-CONT and 90% MI-pGz animals survived (p< 0.01). Four weeks after MI, 80% of the pGz treated animals survived and 50% of the MI-CONT (p< 0.001) .Infarct size prior to randomization was 38±4%. Treatment with pGz for four weeks decreased transmurality of the infarct from 60± 5% for MI-CONT to 48±4% for MI-pGz (p< 0.01). The ratio of left ventricular wall thickness to the MI thickness was significantly smaller in MI-CONT 0.9±0.5 compared to 3.1 ± 0.7 for MI-pGz (p< 0.01), additionally the amount of left ventricular collagen was 35±4% in MI-CONT compared to 22±4% in pGz treated animals (p< 0.01).Ejection fraction and Fractional shortening significantly decreased at 1, 3, and four weeks after MI in both MI-CONT and MI-pGz compared to the immediate post MI time period. Over the four week post MI period, EF decreased an average of 35% from immediate post MI values in MI-pGz, while in MI-CONT the average decrease was 53%. Similarly FS, decreased on average 46% in MI-pGz, and 56% in MI-CONT (p< 0.01) .As expected and in agreement with other studies, MI significantly decreased invasive measures of afterload, preload, integrated myocardial performance, and contractility , 31. FouCompared to sham animals four weeks after myocardial infarction, there was a significant decrease in left ventricular protein content of eNOS (66%), p-eNOS(55%), and a significant increase in iNOS (100%). pGz after MI significantly increased eNOS (78%), p-eNOS (56%) and abrogated the increase in iNOS to only 20% compared with MI-CONT .pGz after MI decreased left ventricular protein content of IL-6 and TNF-α to 33% and 25% respectively of MI-CONT (p< 0.01). pGz also significantly increased the anti-inflammatory signaling cytokine IL-10, 100% of MI-CONT (p< 0.01). Additionally, the ratio of IL-10/ TNF-α was also significantly increased 1.1± 0.05 vs. 0.4±0.05 in MI-pGz vs. MI-CONT (p< 0.01) ..Our study assessed the beneficial functional effects of treatment with pGz after experimental MI in rats. pGz administered one hour daily significantly improved survival and myocardial function. It decreased myocardial fibrosis and transmurality of the infarct, associated with increased eNOS, p-eNOS, and IL-10 along with decreased expression of TNF-α, IL-6 and iNOS.pGz improved survival and contractile performance in this post MI model of heart failure. pGz has been shown to increase myocardial p-eNOS and NO and induce genomic up regulation of eNOS. The present study shows that daily pGz after MI significantly increases eNOS and p-eNOS, while significantly decreasing iNOS expression. Additionally pGz has also been shown to increase myocardial nNOS , 32, 33.Daily pGz treatment commencing 24 hr. after ischemia for four weeks improved the amount of viable left ventricle as evidenced by a higher ratio of left ventricular wall thickness to myocardial infarct thickness, and lower transmural extension of the infarct. Additionally, left ventricular collagen content, a measure of myocardial fibrosis, was reduced by 37% in pGz treated animals. The latter was associated with a decrease in pro-inflammatory cytokines, and increase in anti-inflammatory signaling cytokine.Cytokines and chemokines have been shown to be important signaling molecules for early fibrosis –49. In oDuring myocardial ischemia, TNF- is released from macrophages, monocytes and mast cells and after reperfusion TNF- is expressed and secreted in both cardiomyocytes and fibroblasts. TNF- haPhysical exercise decreases symptoms of coronary heart disease and is at the core of cardiac rehabilitation , 55. ExeTaken together our findings suggest that pGz post MI improves myocardial function, decreases inflammatory signaling, and modifies myocardial remodeling. It is plausible that these changes are at least in part mediated via pGz-induced eNOS up regulation and modulation of an inflammatory phenotype , 59–61.2+ ([Ca2+]i) and Na+ ([Na+]i) overload are prime causes of myocardial injury and death during MI i homeostasis. In addition, there is an important interplay between [Na+]i and Ca2+ handling, so that altered levels of [Na+]i and Na+ transporters can have profound effects on both contractile function and arrhythmogenesis [+]i activates the Na+/Ca2+ exchanger in its reverse mode (Ca2+ in/Na+ out) which in turn further elevates [Ca2+]i [+/H+ exchanger induces acidification of intracellular medium [i and intracellular pH (pHi) in cardiac myocytes depend strongly on [Na]i.Several lines of evidence suggest that intracellular Cauring MI , 63. An oduction , 65, andprotease , all of ogenesis , 68. An  [Ca2+]i  whereas r medium . Thus, bin vitro model of hypoxia and reoxygenation, we showed that pGz partially prevented intracellular Ca2+ and Na+ overload and acidification of the intracellular medium during hypoxia and reoxygenation [2+]i and [Na+]i concentrations by pGz may be explained on the basis of the multiple effects of NO as a cardioprotective molecule [2+], [Na+] and pH. Normalization of Ca2+ homeostasis in salvageable cardiomyocytes might also reduce cell death by necrosis and apoptosis, decreasing the infarct size and reducing remodeling [Using an genation . This famolecule –78. Thesmodeling .Limitations to the present study must be acknowledged. pGz increases serum prostaglandins and adrenomedullin as well as myocardial nNOS, all which are cardioprotective , 80–82. The present study demonstrates that a non-pharmacologic, non-invasive intervention which increases pulsatile shear stress to the vascular endothelium, can protect the heart after MI. There are significant clinical applications to the pGz stimulus. In addition to being a preconditioning stimulus, pGz may serve as a simple therapeutic modality to improve myocardial function after MI. pGz is particularly suited for individuals who cannot or will not exercise due to physical or mental limitations. Since, pGz has been shown to be safe in healthy and diseased human individuals and unlike exercise does not require subject cooperation, translation of its use in humans post MI warrants clinical investigation , 84, 85.S1 Table(PDF)Click here for additional data file.


Systemic telomere length has been associated with measures of diastolic function, vascular stiffness and left ventricular mass mainly in smaller, patient-specific settings and not in a general population. In this study we describe the applicability of these findings in a large, representative population.Peripheral blood leukocyte telomere length (PBL TL) was measured using telomere restriction fragment analysis in the young to middle-aged  Asklepios study population, free from overt cardiovascular disease. Subjects underwent extensive echocardiographic, hemodynamic and biochemical phenotyping. After adjusting for relevant confounders  we found no associations between PBL TL and left ventricular mass index (P = 0.943), ejection fraction (P = 0.933), peak systolic septal annular motion (P = 0.238), pulse wave velocity (P = 0.971) or pulse pressure (P = 0.999). In contrast, our data showed positive associations between PBL TL and parameters of LV filling: the transmitral flow early (E) to late (A) velocity ratio , the ratio of early (e′) to late (a′) mitral annular velocities  and isovolumic relaxation time (P = 0.015). Interestingly, these associations were stronger in women than in men and were driven by associations between PBL TL and the late diastolic components (A and a′).In a generally healthy, young to middle-aged population, PBL TL is not related to LV mass or systolic function, but might be associated with an altered LV filling pattern, especially in women. The progression of acquired cardiovascular diseases (CVD) throughout the human life can typically be tracked by a series of gradual changes in physical, chemical and biological parameters. Levels of systolic blood pressure (SBP), cholesterol, C-reactive protein (CRP), smoking status and sex have all been linked with an increased likelihood of adverse cardiovascular events Telomeres are the nucleotide-protein complexes that shield the chromosomal ends from erosion caused by the end-replication problem during cell division and distinguishes them from double-stranded breaks to prevent chromosomal fusion Although there is still uncertainty about the mechanism(s) by which telomere biology and CVD pathogenesis affect each other, results from both molecular biology and epidemiology have repeatedly shown significant associations Systemic TL has also been linked to LV structure and function but mostly in smaller, patient-specific settings and not in a general population The population-based Asklepios Study offers the advantages of a large sample size and the measurement of numerous potential confounders of TL and CVD. We therefore investigated the relations between systemic TL and proven prognostic parameters All data presented in this paper were collected during the first round of the Asklepios study on successful (cardiovascular) aging. The study comprises 2524 subjects approximately 35 to 55 years of age, free from overt cardiovascular disease or other significant pathologies at baseline. The full description of the study design, inclusion criteria, detailed methodology and population baseline characteristics have been published previously All subjects were fasting, had refrained from smoking for at least 6 hours and were screened for active infection/inflammation before blood sampling. Conventional serum parameters were measured using commercial reagents according to the manufacturers' recommendations on a Modular P automated system , in an ISO 9002 certified reference laboratory RsaI and 10U HinfI followed by gel electrophoresis, Southern blotting, radioactive hybridization of the telomeric fragments and weight markers, phospho-imaging and quantification (expressed as kbp: kilo base pairs) For TL-analyses, whole blood was collected in EDTA tubes cooled to 4°C. DNA isolation was performed within 3 days of collection using the Puregene Genomic Purification Kit . The DNA was long term stored at −80°C before TL measurement in duplicate. 5 µg was digested with 5U 1.7 to account for the effects of both obesity and blood pressure on LVM. We also scaled LVM to the body surface area (g/m2) Blood pressure was recorded using bilateral triplicate measurements  on a rested, sitting subject using a validated oscillometric Omron HEM device . Blood pressure values of these six readings were averaged and the mean value of systolic blood pressure (SBP) is used throughout this study. The subjects underwent a resting echocardiographic examination and a scan of the left and right carotid and femoral arteries . Left ventricular (LV) internal dimensions were measured at end-diastole (LVEDD) with the area-length method. Sphericity was defined as LV width divided by LV length and is expressed as a percentage. Standard 2-D volumetric methods were used to calculate ejection fraction (EF) from end-diastolic and end-systolic LV volumes and to calculate LV mass (LVM). The LVM was scaled allometrically following the recommendations of Chirinos et al. S-F and ΔLS-C are the distances measured from sternal notch to femoral and carotid measuring sites respectively, ΔTQ-F and ΔTQ-C are the time delays between the start of the QRS complex and the onset of systolic flow in the femoral and carotid artery measured by pulse wave Doppler imaging , and early (e′) and late (a′) diastolic septal mitral annulus pulsed wave tissue Doppler (TDI) velocities, pulsed wave Doppler early (E) and late (A) diastolic transmitral flow velocities, E-wave propagation velocity (Vpe) and carotid-femoral pulse wave velocity (PWV). PWV was calculated as follows:Statistical analyses were performed in R 2.15.2. Continuous variables are reported as the mean value ± standard deviation. Means of groups were compared with Student (homoscedasticity) or Welch t-test (heteroscedasticity) as appropriate. To evaluate the contribution of the different confounders to the response variables under study we applied general linear models as implemented in the ‘glm’ function. We report both P-values and the estimated unstandardized effect sizes (b) for TL in these models.Baseline characteristics of the population are presented in Unadjusted models yielded positive linear associations between TL and E/A, e′/a′  and E/e′In all models the positive association between E/A and TL remained significant see , P≤0.002We further examined the components of these ratios (E/A and e′/a′) separately to determine whether the associations were attributable to one of both components or whether the ratios contained additional information beyond the terms they consist of. Surprisingly, the results indicated that neither E  nor e′  were correlated with TL (Model 3). There was however a correlation of TL with A  and a′ .Accordingly, E/e′ was not correlated upon adequate adjustment , neither were other indices of diastolic function: flow propagation velocity of the E-wave , mitral inflow deceleration time  or duration of the atrial contraction . Only IVRT was inversely correlated with PBL TL . Similarly no associations were found with LV structure assessed by LV end-diastolic diameter  and LV mass , body surface area adjusted LV mass  or allometrically height-adjusted LV mass .No significant partial correlation was found between PWV and age-adjusted TL (cf. supra), a result that remained unchanged after additional adjustments . The same is true for pulse pressure (PP) in the Asklepios population .Our main finding is that we can extend a number of previously described associations between PBL TL and cardiovascular structure and function –usually detected in smaller, diseased cohorts - towards a middle-aged, apparently healthy population. After adjustment for confounders, we could not document an association with systolic function, cardiac structure or vascular stiffness. We do however document an intriguing association with certain parameters of LV filling.As mentioned in the introduction, previous reports on the association between TL and indicators of diastolic dysfunction have led to apparently conflicting results. Quartiles of telomere length were shown to correlate with diastolic dysfunction in CAD patients  Analysis of the terms constituting the E/A and e′/a′ ratios in this population suggests that TL was associated with atrial contraction (A and a′), rather than with parameters that could reflect myocardial relaxation or filling pressure, such as E and e′, or reflect myocardial stiffness, such as shortened mitral deceleration time Relaxation and stiffness induce opposite effects on mitral E and A and hence on E/A In this population without overt cardiac disease, we report that PBL TL was not associated with minor changes in systolic parameters such as EF and tissue Doppler movement speed of the septal mitral annulus (s′). Increased LV mass correlates with increased all-cause and cardiovascular mortality With respect to vascular stiffness, no significant associations between PWV (or PP) and TL were found in either sex. Previous studies have reported this association to be significant in men The Asklepios data set does not yet include any longitudinal information thus limiting it to all the drawbacks associated with cross-sectional study designs. Particularly claims of causality can not be made with cross-sectional data alone. Despite the extensive characterization of the Asklepios study, there are some descriptors of CV function which were not measured (e.g. pulmonary venous flow). We cannot exclude the involvement of these factors.There are two general models in which TL is tied to cardiovascular health. The first states that telomere shortening is a primary driver of (cardiovascular) ageing. In support of this model our findings indicate that the associations between some parameters of LV filling and telomere length, are not limited to (chronic) HF patients, but may already be present in a young to middle-aged, apparently healthy population and are more pronounced in women. It is tempting to speculate that telomere biology could be mechanistically involved in the early pathogenesis of diastolic dysfunction and possibly HF by extension. As a matter of fact, in mice, knock-out of the telomere elongating enzyme telomerase, resulted in shortened telomere length over several generations which was associated with the development of overt chronic HF In our data, TL was clearly correlated with E/A, e′/a′ and IVRT but not with other indices of diastolic function. We further explored the relationship between PBL TL and other cardiac and hemodynamic parameters such as sphericity of the ventricle, Vpe, duration of the A-wave and deceleration time (data not shown). No significant associations were found that could help provide clues as to the mechanism by which PBL TL and diastolic function might be linked.The second model states that TL is merely an epiphenomenon, an indicator influenced by conditions in the ageing body. Accelerated telomere attrition in subjects with mildly impaired diastolic function could also be caused by oxidative stress and inflammation, two factors that are known to affect diastolic function as well as telomere length Our data, at present, is insufficient to determine the more likely model. Some of the non-replicated associations might still become apparent with ageing, assuming that a certain threshold of telomere attrition needs to be reached before it has a measurable effect on cardiovascular stiffness or visa versa.Our results show that several parameters of cardiovascular structure and function which have been associated with TL, fail to replicate in a well-phenotyped middle-aged population sample. However, PBL TL is associated with subtle changes in certain parameters of LV filling in this population and these associations are more apparent in women. Further investigation of the underlying biological mechanisms is warranted to provide insights into the relationship between PBL TL, diastolic function and cardiovascular health.


In a direct comparison, the E/E’sr ratio outperformed the ratio of E to early diastolic mitral annular velocity (E’) in predicting progression to the renal endpoint in both univariate and multivariate models (p ≤ 0.039). Moreover, adding the E/E’sr ratio to a clinical model and echocardiographic parameters provided an additional benefit in the prediction of progression to the renal endpoint (p = 0.006). The E/E’sr ratio is a useful parameter and is stronger than the E/E’ ratio in predicting the progression to the renal endpoint, and it may offer an additional prognostic benefit over conventional clinical and echocardiographic parameters in patients with AF.The ratio of early mitral inflow velocity (E) to the global diastolic strain rate (E’sr) has been correlated with left ventricular filling pressure and predicts adverse cardiac outcomes in atrial fibrillation (AF). The relationship between the E/E’sr ratio and renal outcomes in AF has not been evaluated. This study examined the ability of the E/E’sr ratio in predicting progression to the renal endpoint, which is defined as a ≥ 25% decline in the estimated glomerular filtration rate in patients with AF. Comprehensive echocardiography was performed on 149 patients with persistent AF, and E’sr was assessed from three standard apical views using the index beat method. During a median follow-up period of 2.3 years, 63 patients (42.3%) were reaching the renal endpoint. Multivariate analysis showed that an increased E/E’sr ratio (per 10 cm) (hazard ratio, 1.230; 95% confidence interval, 1.088 to 1.391;  Atrial fibrillation (AF) is the most common form of cardiac arrhythmia and its prevalence increases with age, reaching a prevalence rate of 8% in individuals older than 80 years , 2. FurtEchocardiographic measures of left ventricular (LV) function and structure have been reported to predict adverse renal outcomes in advanced chronic kidney disease (CKD) patients from 2-D and tissue Doppler echocardiograhy , 7. We hThis observational cohort study prospectively and consecutively included patients with persistent AF referred for echocardiographic examinations to Kaohsiung Municipal Hsiao-Kang Hospital from April 2010 to July 2012. Persistent AF is defined as AF lasting 7 days, which is confirmed using 12-lead electrocardiography, 24-hour Holter electrocardiography, or electrocardiographic recording during echocardiographic examination. Patients with moderate and severe mitral stenosis, moderate and severe aortic stenosis or regurgitation, severe mitral regurgitation, or inadequate echocardiographic visualization were excluded. In addition, patients with fewer than three eGFR measurements during the follow-up period and patients without a follow-up of more than 6 months after enrollment were also excluded to avoid incomplete observation of changes in the renal function. Finally, 149 patients  were included in this study.The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUH-IRB-20130062). Written informed consent was obtained from the patients, and all clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. The patients also consented to the publication of the clinical details.An experienced cardiologist performed echocardiographic examination on participants respiring quietly in the left decubitus position by using Vivid 7 . The cardiologist was blinded to the clinical data, such as history of hypertension, diabetes mellitus, and coronary artery disease. Two-dimensional and anatomic M-mode images were recorded from the standardized views. The Doppler sample volume was placed at the tips of the mitral leaflets to obtain the LV inflow waveforms from the apical four-chamber view. Pulsed Doppler tissue imaging was performed with the sample volume placed at the lateral and septal corners of the mitral annulus to obtain waveforms from the apical four-chamber view. Early diastolic mitral annular velocity (E’) was averaged from measurements at septal and lateral annuli. The wall filter settings were adjusted to exclude high-frequency signals and the gain was minimized. The LV ejection fraction (LVEF) was measured using the modified Simpson’s method, the LV mass was calculated using the modified Devereux method , the LV LV apical four-chamber, two-chamber, and long-axis views were acquired using a high frame rate (50–90 frames/s). The endocardial border was manually defined using a point-and-click technique. An epicardial surface tracing was automatically generated by the system, creating a region of interest, which was manually adjusted to cover the full thickness of the myocardium in the systolic frame. The ventricular chamber was divided into six segments, and six segmental strain and strain rate curves were analyzed in each apical view. Peak segmental longitudinal systolic strain and early diastolic strain rate measurements were determined from these curves. E’sr was assessed in the 18 LV segments from the three standard apical views. The values in the 18 LV segments were averaged to obtain the mean value for later analysis. The minimum number of LV segments for acceptable E’sr measurements was 15. We used cine loops to determine the beat to be calculated. The raw ultrasonic data, including 15 consecutive beats from the three standard apical views, were recorded and analyzed offline by using EchoPAC version 08 (GE Vingmed Ultrasound AS).The index beat was used to measure LV dimensions, the LVEF, LAVI, LVMI, and E’sr , 16, 17.Demographic and medical data including age, sex, and comorbid conditions were obtained from medical records and interviews with patients. The body mass index (BMI) was calculated as the ratio of weight in kilograms divided by the square of height in meters. Laboratory data were measured from fasting blood samples using an autoanalyzer . Serum creatinine was measured using the compensated Jaffé  method in a Roche/Integra 400 Analyzer  using a calibrator traceable to isotope-dilution mass spectrometry . The valThe renal endpoint was defined as a ≥ 25% decline in eGFR since the enrollment of the patients . For patth-75th percentile) for triglyceride and several serum creatinine measurements. The differences between groups were checked using a chi-squared test for categorical variables and independent t-test for continuous variables. The study participants were stratified into three groups according to tertiles of the E/E’sr ratio. Tertile 1 was considered reference category. Multiple comparisons among the study groups were performed using one-way analysis of variance (ANOVA), followed by a post hoc test adjusted with a Bonferroni correction. Cox proportional hazards analyses were performed to investigate the associations of E/E’sr ratio tertiles and the E/E’sr ratio (continuous data) with progression to the renal endpoint. The adjusted covariates included age, sex, diabetes mellitus, hypertension, coronary artery disease, systolic and diastolic blood pressures, the BMI, fasting glucose, log triglyceride, total cholesterol, hemoglobin, baseline eGFR, uric acid, proteinuria, antihypertensive drug use, antiplatelet agents, anticoagulants, the LAVI, LVMI, LVEF, and EDT. Survival curve for the renal endpoint was derived using Kaplan–Meier analysis. A direct comparison between the E/E’ and E/E’sr ratios was performed in both univariate and multivariate models. Incremental model performance was assessed using a change in the χ2 value. A difference was considered significant at P < 0.05.Statistical analysis was performed using SPSS version 17.0  for Windows. Data are expressed as percentages, mean ± standard deviation, or median (25th-75th percentile: 6–15). The E/E’s ratio was 63.0 ± 21.8 cm. The comparison of baseline characteristics and echocardiographic parameters between patients reaching and not reaching the renal endpoint is shown in One hundred and forty-nine patients were included in this study. The mean age of the patients was 69.8 ± 9.9 years; 104 patients were male and 45 were female. During the follow-up period, the average number of serum creatinine measurements was nine . A comparison of the clinical characteristics and echocardiographic parameters among the study groups is shown in p = 0.011) and adjusted model . p = 0.008) in all patients subdivided according to tertiles of the E/E’sr ratio. A similar pattern of association was observed using the E/E’sr ratio as a continuous variable. An increased E/E’sr ratio was associated with an increased renal endpoint in an unadjusted model  and an adjusted model .The mean follow-up period was 2.3 ± 1.2 years. During the follow-up period, 63 patients (42.3%) reached the renal endpoint. p = 0.284).The use of ACEIs or ARBs was not significantly associated with an increased renal endpoint in univariate analysis . In the multivariate analysis, an increased E/E’sr ratio was independently associated with an increased renal endpoint. In a direct comparison, the multivariate model without E/E’ and E/ E’sr ratios  was not significantly improved by adding the E/E’ ratio , whereas adding the E/E’sr ratio resulted in significant improvement .In the univariate analysis, the E/E’sr ratio was significantly related to the renal endpoint and outperformed the E/E’ ratio of the model in a direct comparison (χ2 = 30.77). Adding the LAVI, LVMI, LVEF, EDT, and E/E’ ratio to the clinical model offered an additional benefit in the prediction of progression to the renal endpoint (p = 0.008). In addition, adding the E/E’sr ratio to the model consisting of the clinical model, LAVI, LVMI, LVEF, EDT, and E/E’ ratio resulted in further significant improvement in the prediction of the renal endpoint (p = 0.006).The incremental value of the E/E’sr ratio in the outcome prediction is shown in In this study, we evaluated the association of the E/E’sr ratio with the progression to the renal endpoint in patients with AF. We observed that the increased E/E’sr ratio was independently associated with an increase in the renal endpoint in patients with AF. In a direct comparison, the E/E’sr ratio outperformed the E/E’ ratio in predicting progression to the renal endpoint in both univariate and multivariate models. Furthermore, the E/E’sr ratio could add a significant incremental prognostic value beyond the conventional clinical and echocardiographic parameters.The first major finding of our study was the identification of the E/E’sr ratio as a risk factor for progression to the renal endpoint in patients with AF. Recent studies have demonstrated that CKD patients with an increased LV filling pressure indicated by an increased LAVI, left atrial diameter, and E/E’ ratio from tissue Doppler echocardiography might have adverse renal outcomes , 22, 23.The second major finding of our study was that the E/E’sr ratio was a useful predictor and was stronger than the E/E’ ratio in predicting progression to the renal endpoint in patients with AF. Recently, we reported that the E/E’sr ratio is a useful parameter and is stronger than the E/E’ ratio in predicting adverse cardiac events in patients with AF . E’ was The third major finding of this study was that adding the E/E’sr ratio to the model consisting of clinical parameters, the LAVI, LVEF, LVMI, EDT, and E/E’ ratio provided an additional benefit in the prediction of poor renal prognosis. Our previous data showed that concentric LVH was associated with progression to dialysis, and that an increased LA diameter and a decreased LVEF and midwall fractional shortening were associated with a rapid renal function decline . In addiThere were several limitations to this study. Because their measurement using the averaging method is time consuming, many echocardiographic parameters, including the LV dimensions, LVEF, LAVI, LVMI, and E’sr, were not obtained by averaging multiple cardiac cycles but were measured according to the index beat. However, several studies have proved that using the index beat to measure certain echocardiographic parameters, including LV systolic and diastolic functions and left atrial parameters, in patients with AF is as accurate as the time-consuming method for averaging multiple cardiac cycles , 16, 17.In conclusion, our results demonstrated that the E/E’sr ratio is a useful parameter and is stronger than the E/E’ ratio in predicting adverse renal outcomes in patients with AF, and it may offer an additional prognostic benefit over conventional clinical and echocardiographic parameters.S1 File(XLS)Click here for additional data file.


Due to improved diagnostic and therapeutic methods, the prognosis of patients with congenital heart disease has improved dramatically , 2. TherExtracorporeal membrane oxygenation (ECMO) is a support system that consists of a pump and an oxygenator Fig. . Blood iIn acute cardiogenic shock, ECMO can be used to provide circulatory and respiratory support and serves as a bridge-to-decision.Fontan circulation, given that the right ventricle can be fully bypassed.Furthermore, because of improved survival to adulthood of patients with congenital heart disease, more re-operations are necessary . ECMO caIn this article we describe the use of ECMO in two adult patients with congenital heart disease and shock. The available literature on the use of ECMO in this particular patient group is reviewed.A 33-year-old female was admitted to our hospital with acute right-sided heart failure caused by severe outflow tract stenosis. As a child she underwent a correction of a tetralogy of Fallot with closure of the ventricular septum defect and correction of the right ventricular outflow tract. Other medical history revealed bleeding disorders, partially explained by factor V Leiden and hepato-splenomegaly. She rapidly developed severe shock for which a peripheral ECMO was placed Fig. . This stShortly after ECMO implantation, leakage and haematoma at the arterial cannula ensued. This led to a low flow state and subsequent multi-organ failure, including acute-on-chronic kidney failure requiring dialysis. The next day, balloon dilatation of the pulmonary tract and pulmonary valve replacement were performed. Due to new-onset left ventricular failure, probably due to stunning, the patient remained dependent on ECMO.Six days after correction of the pulmonary stenosis, the ECMO system could be removed. She was almost ready for transfer to the ward when arterial bleeding occurred at the old insertion site of the femoral cannula. Transfusion of blood products and a surgical correction could not prevent her from dying of haemorrhagic shock.A 38-year-old male with a Fontan circulation after previous correction of a congenital tricuspid atresia, suffered from recurrent atrial tachyarrhythmias. He was admitted to our hospital for a MAZE operation and partial resection of the atria. Due to an increase in intrathoracic pressure caused by mechanical ventilation, the passive pulmonary blood flow of the Fontan circuit was postoperatively impaired, after which he became hypoxic and hypotensive. In order to optimise pulmonary blood flow, treatment with sedatives, inodilators and nitric oxide ventilation was initiated. Progressive shock and multi-organ failure needing dialysis developed. Eight days after ICU admission an ECMO support system was inserted. After installing ECMO, his haemodynamic condition stabilised, although he was still in need of high-dose vasopressins and fluids. Due to progressive multi-organ failure it was decided to withdraw the ECMO after which he died.In this case report the use of extracorporeal membrane oxygenation in two patients with congenital heart disease and shock is described. In the first patient, ECMO was primarily used to optimise the clinical condition before operation. This strategy has been used previously, mainly in patients awaiting cardiac or lung transplantation, but also in children awaiting surgery for congenital heart disease . In thisIn the second case, ECMO was used to treat a patient with cardiogenic shock after cardiac surgery. Although there is more experience in children , its useIn the second patient ECMO was started to treat multi-organ failure and as a bridge-to-decision. The use of ECMO in patients with multi-organ failure is not associated with a positive outcome, probably due to severe organ damage prior to the initiation of ECMO. Our patient suffered from acute renal failure at day one, while ECMO was started at day eight. Earlier initiation of ECMO may improve survival, as this can prevent organ damage .As both cases illustrate, the use of ECMO is not without complications. Haemorrhagic problems, but also sepsis, mediastinitis and thrombosis, are frequent causes of death . InsertiThe use of extracorporeal membrane oxygenation may provide a valuable tool in stabilising patients with congenital heart disease who present with cardiogenic shock, especially when this is due to right ventricular failure . The sysClinicians who apply ECMO should be aware of its serious risks and complications. If manifest multi-organ failure is already present, it is not recommended to start ECMO.


Double-orifice mitral valve (DOMV) is an uncommon congenital anomaly, being present in 0.05% of the general population. The isolated occurrence of this anomaly is very rare and, to our knowledge, no data are currently available on the incidence of an isolated DOMV. A DOMV is characterized by a mitral valve with a single fibrous annulus with 2 orifices opening into the left ventricle (LV). Subvalvular structures, especially the tensor apparatus, invariably show various degrees of abnormality. It can substantially obstruct mitral valve inflow or cause mitral valve incompetence. We present a rare case of nineteen-year-old male who underwent percutaneous mitral balloon commissurotomy in stenotic DOMV. Double-orifice mitral valve (DOMV) is an uncommon congenital anomaly, being present in 0.05% of the general population . It was A 19-year-old male patient presented to us with NYHA class two dyspnea. He had previously been diagnosed with rheumatic heart disease and was put on penicillin prophylaxis. His physical examination showed regular pulse and his blood pressure was 120/86 mm Hg cardiac palpation and percussion was unremarkable; auscultation showed an accentuated first heart sound, and diastolic rumbling murmur. Chest X-ray showed evidence of pulmonary venous congestion. Transthoracic and transesophageal 2-dimensional echocardiography  revealed After informed written consent, BMV was performed using the Inoue-balloon technique. Initially, PA pressure recording was done and LV angiography recorded in RAO view for assessment of mitral regurgitation. Transseptal catheterization and left atrial placement of the balloon catheter were performed in the usual manner . As ball A DOMV was first described by Greenfield in 1876. Banerjee et al. reported the incidence of DOMVs as 0.05% in a total of 13,400 new patients undergoing echocardiographic evaluation. An isolated DOMV is very rare, and to our knowledge, no data are currently available on the incidence of an isolated DOMV [ We have demonstrated that Inoue BMV can be safely and successfully applied to split the fibrous septation in DOMV, resulting in a single enlarged mitral orifice. Our case demonstrates some important tips regarding BMV in such case. First, balloon size used is 4 mm less than normal reference diameter derived from height-based formula. This will prevent tear of leaflets and excessive development of mitral regurgitation. Second; crossing of posteriomedial orifice is easier as it is more caudally situated. Crossing of anteriolateral orifice is not as difficult as previous reports mentioned. All three times we were able to cross anterolatteral orifice without much difficulty and dilatation of which resulted in breaking of midline fibrous band which leads to successful BMV and single enlarged orifice. In summary, in symptomatic patients with stenotic DOMV of incomplete bridge type, Inoue BMV with stepwise dilations applied only to the posteromedial orifice appears to be a safe and effective therapeutic modality.


Several T2-mapping sequences have been recently proposed to quantify myocardial edema by providing T2 relaxation time values. However, no T2-mapping sequence has ever been validated against actual myocardial water content for edema detection. In addition, these T2-mapping sequences are either time-consuming or require specialized software for data acquisition and/or post-processing, factors impeding their routine clinical use. Our objective was to obtain in vivo validation of a sequence for fast and accurate myocardial T2-mapping (T2 gradient-spin-echo [GraSE]) that can be easily integrated in routine protocols.n = 5), 24 h (n = 5), 4 days (n = 5) and 7 days (n = 5) after reperfusion, and heart tissue extracted for quantification of myocardial water content. For the evaluation of T2 relaxation time, cardiovascular magnetic resonance (CMR) scans, including T2 turbo-spin-echo  mapping and T2-GraSE mapping, were performed at baseline and at every follow-up until sacrifice. Five additional pigs were sacrificed after baseline CMR study and served as controls.The study population comprised 25 pigs. Closed-chest 40 min ischemia/reperfusion was performed in 20 pigs. Pigs were sacrificed at 120 min (2 = 0.99) and agreement with no systematic error between techniques. The two T2-mapping sequences showed similarly good correlations with myocardial water content: R2 = 0.75 and R2 = 0.73 for T2-TSE and T2-GraSE mapping, respectively.Acquisition of T2-GraSE mapping was significantly (3-fold) faster than conventional T2-TSE mapping. Myocardial T2 relaxation measurements performed by T2-TSE and T2-GraSE mapping demonstrated an almost perfect correlation (RWe present the first in vivo validation of T2-mapping to assess myocardial edema. Given its shorter acquisition time and no requirement for specific software for data acquisition or post-processing, fast T2-GraSE mapping of the myocardium offers an attractive alternative to current CMR sequences for T2 quantification. Cardiovascular magnetic resonance (CMR) has emerged as a popular and useful tool for noninvasive myocardial tissue characterization . CMR proIt is noteworthy that no T2-mapping sequence has ever been validated for quantification of myocardial water content against direct measurement by a gold standard technique. The validity of T2-mapping sequences for this task has been assumed based on their ability to retrospectively delineate the hypoperfused myocardial territory supplied by the occluded coronary artery (the area at risk). However, regional T2 relaxation time in the post-ischemia/reperfusion area is affected by tissue characteristics , 14, theIn this study, we sought to provide in vivo validation of a sequence for fast and accurate T2-mapping of the myocardium using the gradient-spin-echo (GraSE) technique , which cn = 5, Group 2), 24 h , 4 days  and 7 days  after reperfusion. CMR scans, including T2-TSE mapping (current standard) and T2-GraSE mapping sequences were performed at every follow-up until sacrifice . Five pigs (Group 1) were sacrificed with no other intervention than baseline CMR, and served as controls . Animals were sacrificed immediately after the last follow-up CMR, and myocardial tissue samples from ischemic and remote areas were rapidly collected for determination of water content.Experimental procedures were performed in castrated male Large-White pigs weighing 30 to 40 kg. The study population comprised a total of 25 pigs. The experimental protocol was approved by the Institutional Animal Research Committee and conducted in accordance with recommendations of the Guide for the Care and Use of Laboratory Animals. The study design is summarized in Fig. 2 28 %). Central venous and arterial lines were placed and a single bolus of unfractioned heparin (300 mg/kg) was administered before any further procedure. The left anterior descending coronary artery immediately distal to the origin of the first diagonal branch was occluded for 40 min with an angioplasty balloon introduced thorough a catheter inserted via the percutaneous femoral route. Balloon location and state of inflation were monitored angiographically. After balloon deflation, a coronary angiogram was recorded to confirm patency of the coronary artery. A continuous infusion of amiodarone (300 mg/h) was maintained during the procedure in all pigs to prevent malignant ventricular arrhythmias. In cases of ventricular fibrillation, a biphasic defibrillator was used to deliver non-synchronized shocks. At intermediate follow-up time points, animals were recovered and cared for by a dedicated team of veterinarians and technicians.The protocol of ischemia/reperfusion has been detailed elsewhere . In summ2, and 3 NEX. The imaging parameters for the T2-TSE mapping were FOV 300×300 with and acquisition voxel size of 1.8×1.8 mm2 and slice thickness 8 mm, TR 2 heartbeats, and ten echo times ranging from 4.9 to 49 ms. The imaging parameters for the T2-GraSE mapping were FOV 300×300 with an acquisition voxel size of 1.8×2.0 mm2 and slice thickness 8 mm, TR 2 heartbeats, and eight echo times ranging from 6.7 to 53.6 ms, EPI factor 3. Both T2 mapping sequence where black blood triggered with a trigger delay placed at mid-diastole. Both T2-mapping sequences are schematized in Fig. Baseline CMR was performed immediately before myocardial infarction and subsequently repeated at post-infarction follow-up time points until sacrifice. All scans were performed during free breathing in a Philips 3-T Achieva Tx whole body scanner  equipped with a 32-element phased-array cardiac coil. The imaging protocol included a standard segmented cine steady-state free-precession (SSFP) sequence to provide high quality anatomical references, a T2- turbo spin multi-echo mapping sequence (T2-TSE), and a T2- gradient spin echo mapping sequence (T2-GraSE). The imaging parameters for the SSFP sequence were FOV of 280x280, slice thickness of 6 mm with no gap, TR 2.8 ms, TE 1.4 ms, flip angle 45°, cardiac phases 30, voxel size 1.8×1.8 mmCMR images were analyzed using dedicated software . T2-maps were automatically generated on the acquisition scanner by fitting the SI of all echo times to a monoexponential decay curve at each pixel with a maximum likelihood expectation maximization algorithm. T2 relaxation maps were quantitatively analyzed by placing a wide transmural region of interest (ROI) at the ischemic and remote areas of the corresponding slice in all studies. The masking was defined in the first echo image to improve the contrast between the cardiac muscle and the cavity. Higher T2 values in this interface can be found due to slow flow artifact; therefore, ROIs were carefully placed avoiding those areas from the analysis to minimize contamination on the reported T2 values. Hypointense areas suggestive of microvascular obstruction or hemorrhage were included in the ROI for T2 quantification purposes.Paired myocardial samples were collected within the first 5 min of sacrifice from the infarcted and remote myocardium of all pigs. Tissue samples were immediately blotted to remove surface moisture and introduced into glass containers previously weighed on a high-precision scale. The containers were weighed before and after drying for 48 h at 100 °C in a desiccating oven. Tissue water content was calculated as follows: water content (%) = [(wet weight − dry weight)/wet weight] × 100. An empty container was weighed before and after desiccation as an additional calibration control.cortesti user-written command for Stata. Statistical significance was set at a two-tailed probability level of 0.05. All statistical analyses were performed using commercially available software (Stata 12.0). The authors had full access to the data and take responsibility for its integrity.Normal distribution was checked using graphical methods and a Shapiro-Wilk test. For quantitative variables showing a normal distribution, data are expressed as mean ± standard deviation. For quantitative variables showing a non-normal distribution, data are reported as medians with first and third quartiles. Agreement of T2 relaxation time measurements between T2-TSE and T2-GraSE mapping techniques was evaluated by the square of Pearson’s correlation coefficient, the intraclass correlation coefficient for two-way random effect models, and Bland-Altman analysis . Associap < 0.001). T2 relaxation time measurements obtained by T2-TSE and T2-GraSE mapping at different follow-up points in the ischemic and remote myocardium are summarized in Table Mean study acquisition length was 189 ± 19 s for T2-TSE mapping and 65 ± 8 s for T2-GraSE mapping  technique that can be easily integrated in routine protocols, overcoming some of the limitations of current CMR mapping sequences for myocardial T2 quantification. For this endeavor we developed a closed-chest large animal model of ischemia/reperfusion in which animals had serial CMR scans and were sacrificed at serial time-points after reperfusion for direct quantification of myocardial water content. Two mapping sequences were used to quantify myocardial T2 relaxation time: the well-established reference T2-TSE technique and the newer T2-GraSE technique, which further speeds up the TSE sequence . The traAccurate noninvasive detection and quantification of myocardial edema is of great scientific and clinical interest given the occurrence of edema in several cardiovascular diseases and its usefulness for diagnosis and its correlation with ventricular remodeling and prognosis –22. ManyA number of T2-mapping sequences have been recently proposed as a route to overcoming some of these limitations –9 and prDescriptions of previous T2-mapping sequences have relied on their ability to retrospectively identify the hypoperfused myocardial territory supplied by the occluded coronary artery—the area at risk—and there are no published data validating these techniques against true myocardial water content. Regional T2 relaxation time in the ischemic area can be altered depending on tissue characteristics , 14, theOur data demonstrate similarly good correlation between myocardial water content and both T2-mapping techniques examined. In our study ≈ 25-30 % of T2 relaxation time variance was not completely explained by water content changes, highlighting the influence on T2 values of other tissue characteristics and components , 17 inclIn summary, we provide in vivo validation of a CMR sequence for fast and accurate T2-mapping of the heart using the gradient-spin-echo (GraSE) technique. This approach can be easily integrated in routine protocols since it is available for all equipment, and overcomes some of the limitations of current CMR mapping sequences for T2 quantification.Although tissue changes in the post-I/R myocardium in pigs are similar to those in humans, we cannot rule out the existence of subtle histological differences between human and pig after infarction. As a consequence, the ≈ 30 % of T2 relaxation time variance that was not completely explained by water content changes in the present study might differ slightly from the value in humans. However, experimental studies allow validation, as shown here with the direct quantification of myocardial water content.The pig is one of the most clinically translatable large animal models for the study of myocardial infarction and related issues due to its anatomical and functional similarities to humans , and alsIn this study the ROIs for T2 relaxation time quantification covered the entire wall thickness and were individually adjusted by hand to carefully avoid the right and left ventricular cavities. The ROIs therefore might include different myocardial states  given that reperfused myocardium is a very heterogeneous condition . HoweverWe provide the first in vivo validation of T2-mapping for the assessment of myocardial edema. Given its shorter acquisition time, high accuracy in quantifying T2 relaxation time and no requirement for specific software for data acquisition or post-processing, fast T2-GraSE mapping of the heart is an attractive alternative to current CMR sequences for T2 quantification.


The optimum timing of surgery in asymptomatic patients with severe degenerative mitral regurgitation (MR) is controversial and there are no randomised data to separate early repair from watchful waiting. Chronic volume overload may be a stimulus for progressive myocardial fibrosis, which could potentially be an additional marker for left ventricular (LV) recovery after surgery.In total, 24 patients (mean age 62 +/- 16 years) with degenerative moderate or severe asymptomatic MR with no class 1 indication for surgery were recruited from a dedicated valve clinic in a University Hospital and compared with gender matched controls. All subjects underwent cardiac MRI (1.5T Siemens Avanto) for assessment of LV volumes, deformation (SPAMM tagging), late gadolinium enhancement (LE) and T1-mapping using a modified look-locker inversion recovery sequence (MOLLI) before and 15 minutes post gadolinium (0.1 mmol/Kg) for myocardial extracellular volume (ECV). Global ECV was the average measure from basal and mid short axis slices excluding LGE indicative of infarcted myocardium.Patients with MR (mean regurgitant volume 42 ml ± 20) had impaired longitudinal and circumferential systolic deformation Table  and incrPatients with MR demonstrate a spectrum of myocardial fibrosis associated with reduced longitudinal and circumferential deformation and reduced peak VO2 max. These changes occur before changes in conventional markers of LV structure and function or an increase in BNP. The routine use of CMR may provide a rationale for improved risk stratification in patients with asymptomatic moderate-severe primary MR to optimise the risk/benefit of early surgery.Nil.


Background: Cardiac diffusion tensor imaging (cDTI) contains information on cross-myocyte components of intramyocardial water diffusion. Assuming these to be constrained by the sheetlet and shear layer microstructure of left ventricular myocardium , we hypoWe performed cDTI in vivo at 3 Tesla at end-systole and late-diastole in 11 healthy controls and 11 patients with HCM, with previous late gadolinium enhancement (LGE) for detection of fibrosis.Voxel-wise analysis of diffusion tensors relative to ventricular coordinates showed transmural changes of helix-angle, with no differences between phases or between HCM and controls. In controls, the orientation of the second eigenvector of diffusion (E2A), changed from more wall-parallel in diastole to more wall-perpendicular in systole, in accord with the predicted reorientations of sheetlet populations. HCM hearts showed markedly abnormal global E2A in diastole consistent with impaired relaxation , and minor abnormal global E2A in systole consistent with hypercontraction . In hypertrophic regions, sheetlets retained relatively systolic orientations in diastole, independent of fibrosis, which differed from regions of normal wall thickness .In vivo DTI quantifies cross-myocyte diffusion. We are potentially showing impaired in vivo diastolic reorientation of sheetlet populations in HCM, although further investigation is required as myocardial strain is a possible confounder. Current work includes the measurement of 3D strain in all subjects for assessment of contractility and for strain correction of the diffusion tensor . The perThis work was supported by the National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London.


Myocardial fibrosis is associated with abnormal cardiac remodeling and poor prognosis in patients with hypertrophic cardiomyopathy. Currently, new cardiac MRI (CMR) techniques such as T1-mapping and extracellular volume (ECV) measurement are available to quantify diffuse myocardial fibrosis. We analyzed the size of myocardial fibrosis using pre- and post-contrast T1, ECV and late gadolinium enhancement (LGE) in patients with HCM referenced to normal appearing myocardium and referenced to normal values of healthy volunteers.CMR was performed in 21 patients with HCM  using a 1.5T scanner . Myocardial lesions were assessed on 3 representative short axes of the apex, center and basis of the left ventricle by phase-sensitive inversion-recovery (PSIR) LGE-images, pre- and post-contrast T1 maps and ECV maps. Size of fibrosis was quantified in percent of left ventricular (LV) myocardium by a threshold method relative to normal appearing myocardium using a cutoff >2 SD above normal appearing remote myocardium on all images and relative to normal values assessed from 20 healthy volunteers on T1 and ECV maps. Post-contrast images were obtained after injection of 0.075 mmol/kg Gd-BOPTA. Data were analyzed using the HeAT software.p=0.49). Smaller fibrosis sizes were found on native T1 maps with 14±12%LV (p=0.017) and on post-contrast T1maps with 11±08%LV (p=0.02). When referenced to normal values of healthy volunteers size of myocardial fibrosis was significantly lager with 35±4%LV on native T1, 49±26%LV on post-contrast T1 and 61±16%LV on ECV maps compared to values referenced to normal appearing myocardium .Size of fibrosis relative to remote normal appearing myocardium was 20±15%LV on LGE images and 17±16%LV on ECV maps (When referenced to normal appearing myocardium similar fibrosis sizes were obtained by LGE and ECV, but smaller fibrosis sizes were measured by native and post-contrast T1. Significantly larger fibrosis sizes were found with all mapping techniques when measurements were referenced to normal values of healthy volunteers, indicating a much larger fibrosis burden in HCM patients than currently observed with LGE imaging.


A potential measure of post-ischemic milieu in myocardium subject to acute ischemic injury is to assess the so- called myocardial salvage index (SI) by relating the final infarct size to the initial myocardium at risk (MaR). Cardiac magnetic resonance (CMR) has previously been shown to enable determination of both infarct size using late gadolinium enhancement and MaR using T2- weighted imaging. This technique could thus potentially be used to identify inflammatory responses that could be targeted to accomplish cardioprotection. The aim of this study was to relate SI, as determined by CMR, to the inflammatory response in patients with acute myocardial infarction.Fifteen patients with first-time ST-elevation myocardial infarction were included in the study. All patients underwent primary PCI due to an acute occlusion in one branch of the left coronary artery. Final infarct size and MaR was determined by CMR performed 1 week after the acute event. The ischemic time was defined as the time from pain onset to opening of the occluded vessel. Blood samples were taken for assessment of inflammatory response. Inflammatory cells were analyzed by flow cytometry in a BD FACS Aria. Parameters were gated against control antibody and fluorescence minus one strategy. Cytokine patterns were analyzed by BioRad BioPlex multiplex protein analysis technology.P = 0.2720, R2 = 0.09191). The population was divided into the lowest half of the SI  and the upper half of the SI . The patients' profile of adaptive inflammatory response was characterized by flow cytometry. The two groups did not differ with regard to their T-regulatory response  or NK-cell  response. However, the proportion of TH1 (CD4+ IFNγ+) cells was higher in the group with the lowest SI .in vivo. The study indicates that SI can be used as an evaluator of post- ischemic milieu and that TH1 response is associated with unfavorable post-infarction injury and could therefore be a possible target for future studies to limit infarction size. The current study is, by its size and observational character, important; an argument for rather than a substitute for future interventional studies in this area.This is the first study that identifies inflammatory cell patterns which influence the hostility of the infarction milieu


Positive end-expiratory pressure (PEEP) is commonly used to correct hypoxemia in the ICU. However, PEEP may impair right ventricular functions by increasing its afterload. Speckle tracking imaging (STI) is a new echocardiography strain analysis technique that provides direct assessment of myocardial contractility during systole and diastole. The aim of this study was to evaluate the effects of different PEEP levels on right ventricular functions by using STI in patients undergoing coronary artery bypass grafting surgery.2O PEEP were applied in 5-minute intervals consequently. After stabilization at each PEEP level, four-chamber and two-chamber images of the right ventricle were recorded using TEE. The right ventricle diameter, velocity, longitudinal strain, SR, and fractional area change (RVFAC) were calculated and evaluated from the recorded images.After ethics committee approval and patients' written consent, we prospectively analyzed 20 CABG surgery patients. After initiation of mechanical ventilation and before sternotomy, 5, 10, and 20 cmH2O PEEP, mean RVFAC significantly decreased at 20 cmH2O PEEP (P = 0.001). Right ventricle velocity reduced with incremental PEEP increases (P < 0.05). Mean SR values decreased at 20 cmH2O PEEP when compared with 5 cmH2O PEEP (P = 0.03). Mean right ventricle diameter measurements decreased with incremental PEEP increases; however, this decrease was significantly different between 20 cmH2O PEEP and other two PEEP levels (P = 0.01). The mean right ventricle strain value significantly decreased at 20 cmH2O PEEP when compared with other two PEEP levels (P < 0.001 for both).The mean age of study patients  was 59.7 ± 10.5 years. Intraoperative mean, systolic, and diastolic arterial blood pressures and heart rate were similar at the three PEEP levels. Compared with 5 and 10 cmH2O PEEP levels, right ventricle functions in terms of strain, SR, right ventricle diameter, and RVFAC were significantly impaired at 20 cmH2O PEEP level.Compared with 5 and 10 cmH


Dilated left ventricular volumes (VE) is one of the main factors of poor cardiovascular prognosis with systolic dysfunction. Myocardial fibrosis detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) has been recognized in recent years as an independent prognostic factor in dilated cardiomyopathy, in addition to guiding the etiological diagnosis, and most often the only noninvasive way to differentiate ischemic and nonischemic. The aim of our study was to determine the prevalence of myocardial fibrosis in patients with dilated LV and the morphological and functional differences between ischemic and non-ischemic patterns.We analyzed 114 consecutive patients ≥ 35 years old who were undergoing CMR with LV volume ≥ 95 ml/m2 between March/2013 and August/2014. After identifying the prevalence of myocardial fibrosis, we analysed the morphological and functional differences between patients with ischemic pattern of LGE and non-ischemic pattern of LGE.Patients were 57 ± 11 years old, BMI = 27.6 ± 5.0 kg / m2, LVEF = 43 ± 17%, RVEF = 57 ± 13% and 81% male. Sixty-two (54%) had myocardial fibrosis by LGE, including 36 (58%) with ischemic pattern and 25 (40%) with non-ischemic pattern, and one patient was excluded for presenting the two types of LGE. Among patients with myocardial fibrosis, those who exhibited a pattern of non-ischemic LGE had worse RVEF  and greater RV volumes , with no significant differences in age, sex, BMI, parameters of LV (volumes and EF) or heart rate during CMR performance. Regarding the number of LV segments affected by fibrosis, ischemic patients had more extensive disease .Patients with non-ischemic myocardial fibrosis pattern had higher RV volumes and worse RVEF, and myocardial fibrosis in fewer number of LV segments compared to ischemic pattern. Volumes and EF preserved RV might suggest ischemic etiology in patients under investigation for dilated cardiomyopathy.None.


Inflammation of the sacroiliac joints (SIJ) is a fundamental clinical feature of axial spondyloarthritis (SpA). The anatomy of the irregularly shaped SIJ is complex with an antero-inferior cartilaginous compartment containing central hyaline and peripheral fibrocartilage, and a dorso-superior ligamentous compartment. Several scoring modules to systematically assess SIJ magnetic resonance imaging (MRI) in SpA have been developed. Nearly all of them are based on the cartilaginous joint compartment alone. However, there are only limited data about the frequency of inflammatory lesions in the ligamentous compartment and their potential diagnostic utility in axial SpA. We therefore aimed to evaluate the ligamentous compartment on sacroiliac joint MRI for lesion distribution and potential incremental value towards diagnosis of SpA over and above the traditional assessment of the cartilaginous compartment alone.Two independent cohorts of 69 and 88 consecutive back pain patients ≤50 years were referred for suspected SpA (cohort A) or acute anterior uveitis plus back pain (cohort B). Patients were classified according to rheumatologist expert opinion based on clinical, radiographic and laboratory examination as having nonradiographic axial SpA , ankylosing spondylitis (n = 34), or nonspecific back pain . Five blinded readers assessed SIJ MRI globally for presence/absence of SpA. Bone marrow edema (BME) and fat metaplasia were recorded in the cartilaginous and ligamentous compartment. The incremental value of evaluating the ligamentous additionally to the cartilaginous compartment alone for diagnosis of SpA was graded qualitatively. We determined the lesion distribution between the two compartments, and the impact of the ligamentous compartment evaluation on diagnostic utility.MRI bone marrow lesions solely in the ligamentous compartment in the absence of lesions in the cartilaginous compartment were reported in just 0–2.0/0–4.0 % (BME/fat metaplasia) of all subjects. Additional assessment of the ligamentous compartment was regarded as essential for diagnosis in 0 and 0.6 %, and as contributory in 28.0 and 7.7 % of nr-axSpA patients in cohorts A and B, respectively. Concomitant BME in both compartments was evident in 11.6–42.0 % of nr-axSpA and 2.1–2.4 % of NSBP patients.Assessing the ligamentous compartment on SIJ MRI provided no incremental value for diagnosis of axial SpA. However, concomitant BME in both compartments may help discriminate nr-axSpA from NSBP. Inflammation of the sacroiliac joints (SIJ) is a fundamental clinical feature of axial spondyloarthritis (SpA), and sacroiliitis on magnetic resonance imaging (MRI) represents a major criterion in the Assessment of SpondyloArthritis International Society (ASAS) classification for axial SpA . The anaSeveral scoring modules to systematically assess SIJ MRI in SpA have been developed. Nearly all of them are based on the cartilaginous joint compartment alone –19, and The goals of this study on SIJ MRI in two axial SpA inception cohorts were: (1) to systematically evaluate the frequency of bone marrow edema (BME) and fat metaplasia in the bone marrow of both the cartilaginous and ligamentous SIJ compartment by semi-coronal magnetic resonance images in SpA patients and controls; and (2) to assess the incremental value of the additional evaluation of the ligamentous compartment on diagnostic utility over and above the traditional assessment of the cartilaginous compartment alone in nonradiographic axial SpA (nr-axSpA) patients.The demographical and clinical characteristics of the study sample have been described elsewhere . Two difThere is no standardized or generally accepted gold standard for imaging studies in axial SpA . MRI canThe technical parameters for short tau inversion recovery (STIR) and T1 spin echo (T1SE) sequences of semicoronal MRI SIJ scans have been reported previously . The MRIThe evaluation of the cartilaginous compartment on SIJ MRI followed a standardized module , 17, 23 The assessment of the ligamentous compartment on SIJ MRI also comprised a global and a lesion-based section. Readers reported in the global section whether the additional evaluation of the ligamentous joint compartment provided an incremental value  over and above the global assessment based on the cartilaginous joint compartment alone. Readers also recorded whether the additional evaluation of the ligamentous joint compartment changed diagnosis (from nonSpA to SpA or vice versa) or altered the confidence in a diagnosis of SpA based on MRI assessment of the cartilaginous compartment alone. The complex anatomy of the ligamentous joint compartment precluded an evaluation per joint quadrants. BME and fat metaplasia were recorded as present/absent if observed in bone marrow on any slice of the ligamentous compartment. Erosions were not scored in the ligamentous compartment because they cannot be discriminated reliably from physiological insertions of SIJ ligaments.Differences in demographic and clinical characteristics between cohorts A and B were assessed by Fisher’s exact test for nominal and Wilcoxon test for continuous variables. We calculated the mean percentage of patients and controls over five readers showing ≥1 BME or ≥1 fat metaplasia lesion (dichotomously indicating 'presence' or 'absence' of lesions) in the cartilaginous and ligamentous SIJ compartment, respectively.Interobserver reliability of MRI lesions was evaluated in both joint compartments because it might be expected that detection of lesions in the ligamentous compartment would be less reliable due to its more complex anatomy. Percent agreement (positive and negative concordance) among the 10 possible reader pairs for each group of study subjects, and weighted Cohen’s kappa values for five readers jointly per cohort  were useWe calculated the mean percentage of patients and controls over five readers who showed ≥1 MRI lesion both in the cartilaginous and ligamentous compartment, and in only one or in none of the two joint compartments, separately for BME and fat infiltration. The constellation of lesions observed solely in the ligamentous compartment without corresponding lesions in the cartilaginous compartment was further analyzed regarding agreement among the five readers.We calculated the mean percentage of patients and controls over five readers where the additional evaluation of the ligamentous compartment was regarded as essential, contributory or noncontributory for diagnosis of SpA versus nonSpA beyond the assessment of the cartilaginous compartment alone. We further analyzed whether the additional evaluation of the ligamentous compartment led to a switch in diagnosis . We also assessed how often confidence in diagnosis of SpA increased from 5–7 to 8–10 following additional evaluation of the ligamentous compartment, and we expressed this as mean percentage of patients and controls over five readers.We used R Core Team 2014, version 3.1.0, Vienna, Austria, for statistical analysis .Table MRI bone marrow lesions were less frequent in the ligamentous than cartilaginous compartment, consistently across both cohorts, all study groups, and for both lesion types. Among nr-axSpA patients, BME in the ligamentous/cartilaginous compartment occurred in 42.0/83.0 % and 11.6/45.2 % for cohorts A and B, respectively, and fat metaplasia in 21.0/47.0 % and 25.2/43.9 %, respectively  than in nr-ax-SpA  patients. However, a comparable difference in lesion frequency between AS and nr-axSpA groups was also recorded for the cartilaginous compartment. BME in the cartilaginous compartment was reported in 88.0 and 74.2 % of AS and 83.0 and 45.2 % of nr-axSpA patients in cohorts A and B, and fat metaplasia in 66.0 and 79.2 % of AS and 47.0 and 43.9 % of nr-axSpA patients.Agreement by percent concordance among 10 possible reader pairs for BME and fat metaplasia showed no systematic discrepancies between the two joint compartments across both cohorts Table . In cohoMRI lesions occurring concomitantly in the cartilaginous and ligamentous SIJ compartment were recorded more frequently in AS than in nr-axSpA patients, both for BME and fat metaplasia and across both cohorts A and B  , which may assist towards discrimination of the two conditions  than in patients with early undifferentiated SpA (26–43 %) . A studyAgreement for BME was substantial both in the cartilaginous and ligamentous compartment  in cohort A. In cohort B, agreement was substantial in the cartilaginous compartment (kappa 0.64) and fair in the ligamentous compartment (kappa 0.37), the latter finding possibly attributable to a much lower frequency of ligamentous BME lesions compared to cohort A. A Dutch study on SIJ MRI in 68 patients with inflammatory back pain, but lacking a control group, showed comparable agreement on BME in the cartilaginous compartment (kappa for two readers for right/left SIJ 0.73/0.65), but a lower agreement in the ligamentous compartment (kappa for right/left SIJ 0.49/0.38) [An additional assessment of the ligamentous SIJ compartment provided no incremental value for diagnosis of axial SpA nor for confidence with this diagnosis over and above the traditional approach, in which only the cartilaginous compartment of the SIJ is evaluated. This finding is most likely due to a nearly complete redundancy between ligamentous and cartilaginous SIJ MRI lesions. There was virtually no isolated inflammation in the ligamentous SIJ compartment alone without associated lesions in the cartilaginous compartment. This observation is in line with the results of a previous report in which only 1 of 37 patients fulfilling the ESSG criteria showed isolated inflammation of just the ligamentous SIJ compartment . HoweverA study limitation shared with most other evaluation modules of SIJ MRI is the lack of additional semi-axial slices, as proposed by the Danish working group –22, 39. However, data are lacking whether additional semi-axial slices facilitate evaluation of the ligamentous compartment leading to enhanced diagnostic utility of SIJ MRI in nr-axSpA. Two of our findings, that question a potentially relevant role of additional semi-axial slices, are the low frequency of ligamentous SIJ inflammation in early disease, and the very high association of inflammatory features in both compartments. Another challenge is the technically difficult assessment of the ligamentous compartment. Its irregular contour prevents a quadrant-based evaluation similar to the cartilaginous compartment, and defining a reproducible demarcation where the ligamentous compartment ends posteriorly is challenging.Assessment of MRI bone marrow lesions in the ligamentous SIJ compartment provided no incremental value towards diagnosis of nr-axSpA. Moreover, it did not enhance confidence in the diagnosis over and above the traditional evaluation of the cartilaginous compartment alone, when using semi-coronal images. The most likely explanation was a high level of redundancy with MRI BME and fat metaplasia lesions occurring concomitantly in the ligamentous and cartilaginous compartments. However, BME observed simultaneously in both SIJ compartments might facilitate the clinically relevant discrimination between nr-axSpA and NSBP patients because the latter showed concomitant inflammation in both compartments only very rarely.


We report a female patient with asymptomatic cor triatriatum sinister, associated with 4q34.3 deletion. Her child, carrying the same imbalance, suffers from tetralogy of Fallot. To the best of our knowledge, this is the first reported case of cor triatriatum associated with deletion of the long arm of the chromosome 4; furthermore, the majority of patients with chromosome 4 long arm syndrome have de novo deletions and only few familial cases have been reported so far.  Terminal deletion of chromosome 4q is a rare condition with an estimated incidence of 1 : 100,000 .Moreover, a high frequency of congenital heart disease (CHD) has been demonstrated in patients with 4q-syndrome, particularly in those with deletions encompassing the region 4q33.We present two patients, a mother and her son, carrying the same 4q34.3 deletion but with different phenotypes.The child suffers from tetralogy of Fallot, while the mother has nonobstructive cor triatriatum sinister. This latter is one of the rarest congenital cardiac malformations, in which the left atrium is divided by a thin membrane into two chambers communicating through one or more openings.Our institution follows a 1-year-old male child with tetralogy of Fallot, born to a 35-year-old woman after an uncomplicated pregnancy. He is the only child of unrelated parents. The family history was negative for CHD. Furthermore he had mild developmental delay and soft dysmorphic features, consisting in hypertelorism, low set ears, broad nasal bridge, and receding chin, while limbs and fingers were normal. Cytogenetic analysis of the proband and his parents was performed on cultured lymphocytes, using a validated oligonucleotide array comparative genomic hybridization Human Genome CGH 180 K Oligo Microarray kit  with a mean 13 Kb resolution.A male karyotype with a terminal 118 Kb deletion in the long arm of chromosome 4  was demonstrated in the proband. Paternal chromosomes were normal. On the other hand his phenotypically and intellectually normal mother was found to carry the same imbalance. She underwent a cardiac examination in order to rule out a subclinical congenital malformation. Cardiac auscultation revealed a systolic murmur in the mitral area. The ECG was normal. Transthoracic echocardiography showed a thin perforated membrane dividing the left atrium into two chambers Figures . Color-DWe report a boy with tetralogy of Fallot in whom del4q34.3 was evidenced and the same imbalance was detected in his mother that has a nonobstructive cor triatriatum sinister.Deletion of chromosome 4 long arm is a rare genetic aberration that determines the “chromosome 4q-syndrome,” characterized by some common phenotypic features consisting of mental retardation, dysmorphic facial anomalies, cleft palate, limb malformations, genitourinary, and gastrointestinal and cardiac anomalies –4.Usually deletions proximal to 4q31 determine more severe malformations that often lead to miscarriage. On the other hand, patients with more distal deletions (4q33-4q34) are less severely affected, with minor abnormalities and mild mental retardation .Very often patients with 4q-syndrome have cardiac malformations; particularly defects of right ventricular outflow tract have been reported in 35% of these patients , 2, 4, 5The highest incidence of CHD, including pulmonary atresia, tetralogy of Fallot, ventricular septal defect, and aortic coarctation, has been found in patients with 4q33 deletion –7.It has been postulated that congenital cardiac anomalies, mainly right outflow tract obstructions, are associated with deletions or duplications of gene of Heart and Neural crest Derivatives-expressed 2 (HAND2), mapped to 4q33 –9.We describe two different cardiac malformations associated with del-4q34.3, namely, tetralogy of Fallot in a child and cor triatriatum in his mother. These cases present some interesting aspects; firstly in patients with 4q34 deletions CHD are quite uncommon –12 and iTetralogy of Fallot is part of the spectrum of right ventricle obstruction; on the contrary cor triatriatum sinister is a left heart obstruction.Cor triatriatum is very uncommon, representing only 0.1% of congenital cardiac malformation. In cor triatriatum the left atrium (cor triatriatum sinister) or the right atrium (cor triatriatum dexter) is divided into two chambers by a fibromuscular membrane. In cor triatriatum sinister, which is more common than dexter, the proximal atrial chamber receives the pulmonary veins, while the distal chamber communicates with the ventricle through the mitral valve.The thin membrane, subdividing the atrium, usually has one or more openings.When left ventricular filling is hindered by the diaphragm the anomaly determines symptoms of heart failure since infancy; otherwise some patients with nonobstructive lesions do not experience symptoms and disease can be diagnosed incidentally.Further studies will be required to better characterize the cardiac anomalies associated with this 4q-syndrome.