Cocaine is an addictive, sympathomimetic drug with potentially lethal effects. The prevalence and features of cocaine cardiotoxicity are not well known. We aimed to assess these effects using a comprehensive cardiovascular magnetic resonance (CMR) protocol in a large group of asymptomatic cocaine users.Consecutive , non-selected, cocaine abusers were recruited and had a medical history, examination, ECG, blood test and CMR. The CMR study included measurement of left and right ventricular  dimensions and ejection fraction (EF), sequences for detection of myocardial oedema and late gadolinium enhancement (LGE). Images were compared to a cohort of healthy controls.Years of regular cocaine use were 13.9 ± 9. When compared to the age-matched healthy cohort, the cocaine abusers had increased LV end-systolic volume, LV mass index and RV end-systolic volume, with decreased LVEF and RVEF. No subject had myocardial oedema, but 30% had myocardial LGE indicating myocardial damage.CMR detected cardiovascular disease in 71% of this cohort of consecutive asymptomatic cocaine abusers and mean duration of abuse was related to probability of LV systolic dysfunction. Cocaine is a highly addictive sympathomimetic drug with potentially lethal effects ,2. The aCocaine cardiotoxicity appears multifactorial through several mechanisms involving the development of ischemia and infarction , ventricThe majority of studies that have assessed the prevalence and pattern of cardiovascular involvement due to cocaine abuse are autopsy series  or retroCardiovascular magnetic resonance (CMR) is the current gold standard technique for the assessment of ventricular dimensions and function, with high accuracy and reproducibility and reference values established for both the left  and righTherefore, we aimed to prospectively assess the presence and pattern of cardiovascular involvement due to cocaine abuse in consecutive, asymptomatic cocaine abusers (CA) with a comprehensive CMR protocol, adjusting for the effect of other concomitant variables such as tobacco or alcohol abuse.This was a prospective study for which we recruited consecutive asymptomatic CA  who fulfilled the criteria for cocaine addiction or abuse , who wer2 and ≥ 30 kg/m2, respectively. Diabetes mellitus was defined according to the ADA 2008 criteria [Data from the patients’ medical records were collected. Hypertension and dyslipidemia were defined according to the current guidelines ,21. Paticriteria ; from 20criteria . Family Cocaine abuse or dependence was ascertained using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)  and by dThese included recording of weight, height, heart rate, blood pressure and a cardiovascular routine evaluation. Blood sampling was performed for blood count, usCRP, fasting glucose levels, lipid profile, GOT, GPT, GGT and fibrinogen. Urine cocaine screening tests for the cocaine metabolite benzoylecgonine  were done. A rest electrocardiogram was obtained prior to the CMR scan.The study was done in a 3 T scanner . Images were obtained using a 32-channel surface array coil with multitransmit parallel radiofrequency transmission. Multislice dark blood and bright blood single shot sequences were acquired. High resolution balanced SSFP cine sequences with retrospective gating were obtained in the usual cardiac views as well as in an oblique sagittal plane of the aorta. Typical parameters were TR = 3.2 ms, TE = 1.49 ms, field of view = 360 mm × 290 mm, matrix size = 256 × 224 (in-plane resolution 1.4 mm × 1.3 mm), slice thickness 7 mm, slice gap 3 mm, flip angle 30°, temporal resolution 28 ms, 40 phases. STIR sequences in end-expiration were acquired in the same views (TR/TE/TI/ matrix/slice thickness = 1800 ms/75 ms/190 ms/ 220 × 180/7 mm). High resolution transverse multislice T2 FSE sequences of the thoracic aorta were obtained (TR/TE/matrix/slice thickness/gap = 2000 ms/85 ms/340 × 290/7 mm/3 mm).In the first 48 subjects, dipyridamole (0.84 mg/Kg in 6 minutes) stress myocardial perfusion images were acquired by using a saturation prepared gradient-echo sequence , in three ventricular short-axis sections during gadolinium bolus administration (0.1 mmol/Kg). Images were also acquired at rest at the end of the protocol. In the subsequent 46 subjects the same myocardial perfusion sequence was acquired at rest.Finally, segmented inversion-recovery sequences (IR-TFE) were acquired for detection of late gadolinium enhancement (LGE), starting at least 5 minutes after contrast administration, and in the same views as the functional study (TR/TE/matrix/segments = 6.2 ms/3.1 ms/ 240 × 210/25). The TI was adjusted to the value required to null the signal from the healthy myocardium. Whenever LGE was seen, the same sequence with swapped phase-encoding direction and different TI was repeated to rule out artifacts.All the images were analysed with dedicated software . Analysis was carried out by two observers with at least 10 year experience in CMR. The following variables were quantified: left and right  ventricular end-diastolic (EDV) and end-systolic (ESV) volumes, LV mass, end-diastolic wall thickness, end-diastolic and end-systolic diameters, left atrial (LA) maximum anteroposterior diameter and area. Regional wall motion abnormalities and myocardial edema were investigated. Myocardial perfusion was visually assessed. Localization, pattern of transmural extent and quantification of LGE were obtained. Additionally, aortic and pulmonary trunk dimensions were measured and aortic plaques detected.A control group of 80 healthy subjects  of the same age deciles as the study subjects (20-60 years of age), belonging to a cohort whose normal values of reference have been previously published elsewhere ,15, wereThe data obtained were transferred into a database program SPSS 17.0 . All the study variables were tested for normality with the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± standard deviation, categorical variables were presented as percentages. Student-t test was used with the continuous Gaussian variables or, alternatively, the Wilcoxon test was employed. Qualitative variables were analyzed with the Chi-square test. Analysis of variance (ANOVA) was used whenever more than two levels of a variable were observed. Logistic regression using stepwise method was employed to analyze the odds ratio (OR) of the severity variables with significant results in the univariate analysis.Initially, 132 CA were recruited. For some reasons , which minor repolarization abnormalities such as flat T waves or < 0.5 mm ST depression in 26 patients (27%), significant repolarization abnormalities in the inferior leads in 4 CA and in frontal leads in another 3. ECG criteria of LV hypertrophy (LVH)  were preIntraobserver and interobserver variability were assessed for LV and RV parameters in a subset of 15 CA. Intraobserver variability was below 4% for left ventricular parameters and below 5% for right ventricular parameters. Typical interobserver variabilities were below 5% and 5.5% respectively.2, P < 0.01) and the LV mass index was increased  in the CA group. The relative wall mass was also significantly increased . No relation was found between blood pressure levels and LV mass. The LV ejection fraction (EF) was decreased .The results of the CMR scans in the CA group were compared to those of the age-matched control group Table . The LVE2, P < 0.01). Accordingly, there was a significant decrease in RVEF .With regard to the RV, interestingly and similarly to the LV, the RVESV was significantly increased in the CA group  had increased LVEDV and 29 CA 31%) had an increased LVESV. Furthermore, 32 CA 34%) showed decreased LVEF, the lowest being 48%  showed focal myocardial gadolinium enhancement. LGE extension was very limited, affecting 1 myocardial segment in 27 CA, and 2 segments in the remaining 2 CA. In 1 CA, LGE was subendocardial and located in the inferior wall, in another 2 CA a subepicardial pattern was found, it was midmyocardial in 14, and finally, it was located at the inferior RV insertion point in the remaining 10 CA. The mean percentage of focal myocardial fibrosis was 0.26 ± 0.5% of LV mass   for developing aortic plaques. There was a poor correlation between CMR and ECG for detection of LVH. Only 3 patients with LVH on CMR had electrocardiographic criteria of LVH, while 4 patients with electrocardiographic LVH had normal LV mass on CMR. The presence of ECG abnormalities was not associated with a higher percentage of regional wall motion abnormalities, LGE, LVH or dilatation, however there was a higher percentage of patients with LV systolic dysfunction among those with abnormal ECG findings  and with aortic dilatation (P < 0.05), and borderline significantly for RV systolic dysfunction (P =0.06). Logistic regression showed that each year of regular cocaine use increased the risk of mild LV systolic dysfunction by nearly 10% . No significant differences were found in CMR findings between nasal, intravenous or smoked cocaine users. Likewise, no correlation was found between CMR findings and time since last use.Among cocaine abusers, 51% of subjects had concomitant alcohol abuse or dependence. No significant differences in ventricular dimensions and function were seen according to severity of alcohol consumption.We have used CMR at 3 T to describe the adverse effects caused by chronic cocaine consumption on the cardiovascular system in asymptomatic CA, compared to a group of healthy subjects, which consist mainly in mild LV dilatation, dysfunction and hypertrophy, RV dysfunction and focal myocardial fibrosis. Importantly, the RV was affected to some degree in nearly 25% of CA. Overall, some degree of cardiac involvement was shown in 71% of CA, and LV dysfunction was related to number of years of regular cocaine use, which may have practical importance in these patients’ medical care. It has been previously shown that cocaine is cardiotoxic in both symptomatic  and asymWe observed mild LV dilatation in 31% of the subjects included. This is in concordance with previous literature ,35. Whet6 but in asymptomatic abusers this had not been reported before. Unfortunately, so far no single mechanism has been proven to be responsible for LVH in this setting but some have been suggested, including the presence of frequent hypertensive peaks, direct stimulation of myocardial α-adrenergic receptors, and increased expression of cardiomyocyte proteins mediated by protein kinase-C and calcium/calmodulin kinase II-dependent mechanisms.With regard to LV anatomy, we found a pattern of concentric LV remodelling in 13% of subjects and LV hypertrophy in 30%, which was in 15 cases concentric and in another 13 eccentric, not related to blood pressure levels. This finding may have prognostic value given the different prognosis that each pattern of LVH or remodeling has . AutopsyAnother interesting finding in our study is the presence of RV involvement in these subjects. We observed RV dilatation in 13% of subjects. Likewise, RV systolic dysfunction was observed in 17% of subjects, which was in all cases global. Again, though the reason for this remains unclear, similar systemic mechanisms to those suggested for LV dysfunction could probably be applicable to the RV.We did not find signs of acute myocarditis such as increased focal myocardial signal intensity in the STIR sequences. In contrast to our findings, both autopsy ,38 and cWe could only assess stress myocardial perfusion in 48 CA. Still, we did not find any hypoperfusion pattern suggestive of significant epicardial coronary artery disease but only small, subendocardial, short-lasting perfusion defects in 4 CA, not related to ventricular dilatation or dysfunction in any case. Though invasive coronary angiography was not performed, we hypothesize that these perfusion defects could represent small vessel disease, which is a frequent finding in CA .We found focal myocardial LGE in 30% of our patients. One patient showed a subendocardial pattern suggestive of myocardial necrosis, but not associated with a wall motion abnormality. In another two patients LGE was subepicardial, suggestive of past myocarditis. Finally, it was midmyocardial in 14 and in another 10 it was located in the inferior RV junction. The presence of coronary disease is not a sine qua non for the development of cardiac injury and late gadolinium enhancement. A previous publication in a casual cocaine user has demonstrated multiple spots of midmyocardial LGE taken as potential evidence of cocaine-induced vasoconstriction of coronary arterioles . FurtherFinally, we report the unexpected finding of LGE of the inferior RV insertion point in 10 CA. This particular pattern of LGE has been previously associated with adverse outcome in pulmonary hypertension, but we did not find RV wall motion abnormalities or pulmonary trunk dilatation in these patients, though this pattern was as frequent as midmyocardial LGE in patients with RV systolic dysfunction.We observed ECG abnormalities of variable degree in nearly half of the subjects, similar to other authors ,43-45, mThough it makes sense to quantify the amount of cocaine use as a marker of the severity and duration of cocaine abuse, there is no widely accepted quantitative variable. Cocaine abusers find it very difficult to recall accurately their usage. Also, as cocaine addiction may span many years, the abuse level can vary considerably. We chose number of years of regular cocaine use among a number of potential variables because this is simple for use in these patients, and also because it seemed the most accurate reflecting severity of cocaine abuse. We found that this variable was associated with the likelihood of cardiac involvement, reflecting cocaine cardiotoxicity, which may have practical utility for the overall medical care of these patients.In our study, 51% of cocaine users had concomitant alcohol abuse or dependence. This proportion falls within the published ranges of 30-75% ,48. We dOur study population may not be representative of subjects with only a recreational use of cocaine, or those who by their living standards have no financial problems maintaining their addiction who do not suffer economic, health or social problems, and thus may not seek medical care. Although we recruited consecutive patients, there is a potential selection bias as they were referred from the addictions treatment unit, which might indicate a more severe addiction or higher suspicion of heart disease. We cannot rule out coronary artery disease as a potential explanation to our findings as we did not perform relevant diagnostic investigations. We could not compare LGE findings in addicts with those of healthy subjects because we did not perform LGE in controls as that was not the scope of that particular study. Also, echocardiography was not performed so potential causes for RV dysfunction such as pulmonary hypertension could not be ruled out. Still, though 6% of addicts showed mild pulmonary trunk dilatation, we did not observe significant tricuspid regurgitation in the cine sequences in any of them. Finally, though the sample size of our study is one of the largest published to date, it remains fairly limited in power to detect small differences from normal. However, cocaine addicts are a difficult group of patients to study and are not reliable attenders for investigations and research.CMR detected cardiovascular disease of variable degree in 71% of this cohort of consecutive cocaine abusers. The main findings were a decrease in systolic function of both left and right ventricles, an increase of left ventricular mass and the presence of focal fibrosis. There was a significant association between years of cocaine use and probability of LV systolic dysfunction.The authors declare that they have no competing interests.AMM: conception and design, data collection, analysis and interpretation of data, drafting of the manuscript, final approval. CR: conception and design, data collection, drafting of the manuscript, final approval. JC-S: design, critical review of the manuscript, final approval. BI: design, data collection, critical review of the manuscript, final approval. MG: design, data collection, drafting of the manuscript, final approval. JS: conception and design, analysis and interpretation of data, critical review, final approval. VB: conception and design, critical review, final approval. DP: conception and design, interpretation of data, critical review of the manuscript, final approval.Video S1. Cine sequence in the 4-chamber view of a CA showing mild left ventricular systolic dysfunction. LVEF was 49%.Click here for fileVideo S2. Cine sequence in the 4-chamber view of a CA with concentric LVH. LVMi was 96 g/m2 and the relative wall mass was 1.18.Click here for fileVideo S3. Cine sequence in the 4-chamber view of a CA with eccentric LVH. LVMi was 95 g/m2 and the relative wall mass was 0.91.Click here for fileVideo S4. Cine sequence in the 4-chamber view of a CA showing right ventricular systolic dysfunction. RVEF was 44%.Click here for fileVideo S5. Cine sequence in the 4-chamber view of a CA showing mild biventricular systolic dysfunction. LVEF was 50% and RVEF was 46%.Click here for file


Myocardial T1 relaxation times have been reported to be markedly abnormal in diverse myocardial pathologies, ascribed to interstitial changes, evaluated by T1 mapping and calculation of extracellular volume (ECV). T1 mapping is sensitive to myocardial water content of both intra- and extracellular in origin, but the effect of intravascular compartment changes on T1 has been largely neglected. We aimed to assess the role of intravascular compartment on native (pre-contrast) T1 values by studying the effect of adenosine-induced vasodilatation in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR).42 subjects (26 patients with severe AS without obstructive coronary artery disease and 16 controls) underwent cardiovascular magnetic resonance at 3 T for native T1-mapping (ShMOLLI), first-pass perfusion  at rest and during adenosine stress, and late gadolinium enhancement (LGE).AS patients had increased resting myocardial T1 , reduced MPRI , and increased left ventricular mass index (LVMI) and LGE volume compared to controls. During adenosine stress, T1 in AS was similar to controls , possibly reflecting a similar level of maximal coronary vasodilatation in both groups. Conversely, the T1 response to stress was blunted in AS . Seven months after AVR (n = 16) myocardial T1 and response to adenosine stress recovered towards normal. Native T1 values correlated with reduced MPRI, aortic valve area, and increased LVMI.Our study suggests that native myocardial T1 values are not only influenced by interstitial and intracellular water changes, but also by changes in the intravascular compartment. Performing T1 mapping during or soon after vasodilator stress may affect ECV measurements given that hyperemia alone appears to substantially alter T1 values. Myocardial T1 determination using cardiovascular magnetic resonance (CMR) is a technique that can be used to provide a quantitative measure of myocardial water, without the need for exogenous contrast agents ,3, oedemDespite the rapidly growing applications, the T1 sensitivity to detect disease is not fully understood and the measurements depend somewhat on the particular choice of methods –14. In pIn this work, we aimed to examine the impact of induced vasodilatation on the native T1 values following adenosine stress perfusion. This allowed assessment of the potentially reduced vascular reactivity in AS due to coronary microvascular dysfunction . We also2, peak aortic valve gradient was 64 mmHg and there was no other significant valvular pathology on echocardiogram. Patients were excluded if they had systolic blood pressure (BP) >160 mmHg and diastolic BP >90 mmHg, LVEF <50%, contraindications to CMR, glomerular filtration rate <60 ml/min, underlying cardiomyopathy or known history of CAD. Of these patients, 16 had a repeat CMR scan 7 months after AVR. Ten patients did not have a follow-up scan due to reasons such as death (2 patients), pacemaker implantation (1 patient), hospital admission due to unrelated to cardiac causes (1 patient), lost to follow-up (3 patients) and declined a repeat scan (3 patients). In addition, healthy volunteers with no prior cardiac history or known cardiac risk factors, not on any cardiovascular medications and with a normal ECG served as controls. All subjects gave written informed consent to participate in the study and ethical approval from the National Research Ethics Service committee South Central – Berkshire was granted for all study procedures.We prospectively recruited 26 patients with severe AS without obstructive coronary artery disease (CAD) on invasive coronary angiography scheduled prior to AVR. Severe AS was diagnosed based on the previously established criteria . BrieflyCMR was performed in a 3 Tesla MR system . Study participants were instructed to avoid caffeine-containing food and drinks for at least 24 hours prior to CMR scan. Cine imaging was performed using standard methods . At restAnalysis of cardiac volumes, function and mass was performed according to the standard methods . AVA wast-test, the chi-square test, or Fisher’s exact test as appropriate. Bivariate correlations were performed using Pearson’s or Spearman’s method as appropriate. Comparisons between pre- and post-AVR measurements in AS patients and rest and stress T1 values were performed using 2-tailed paired t-test. Comparisons between AS patients and controls at baseline and post-AVR were performed using Student t-test or Mann–Whitney U test as appropriate. A P-value <0.05 was considered significant. All statistical analyses were performed with IBM SPSS Statistics, version 20.All data are expressed as mean ± standard deviation or median (interquartile range), and checked for normality using Kolmogorov–Smirnov test. Categorical data are presented as numbers and percentages. Comparisons between the 2 groups were performed using Student Patient characteristics during the baseline examination are summarized in Table CMR results are also summarized in Table Both AS patients and controls had equivalent rises in rate pressure product (RPP) during adenosine stress  and .Importantly we now report that T1 values were significantly increased during adenosine stress in both AS patients  and normal controls . Interestingly, both groups exhibited similar maximal T1 values during adenosine stress . Given the T1 increase at rest, the stress response was blunted in AS patients, as expressed by significantly smaller absolute ΔT1  and percentage of ΔT1 . As expected, myocardial perfusion reserve was significantly reduced in AS patients when compared to normal controls .r = 0.59, p < 0.001) and absolute LGE volume  but not LGE volume as % of LV mass . Furthermore, T1 values had an inverse correlation with MPRI  and AVA . These relationships and their significance were preserved when the correlation analysis was repeated excluding segments showing focal LGE (results not shown).Resting T1 values increased with increasing LVMI  showed weak negative correlation with LVMI but no significant correlation with MPRI or LGE.These results are summarized in Table Increased myocardial T1 values has previously been linked to expansion of interstitial space owing to interstitial fibrosis based on native T1 and ECV measurements using post-contrast T1 techniques ,26. In tT1-mapping is typically known for edema imaging and as a surrogate for diffuse myocardial fibrosis in the absence of other causes of interstitial expansion (such as edema and amyloidosis)  to studyet al. who demonstrated markedly increased resting blood flow and reduced coronary flow reserve in aortic valve disease, but maximum flow during stress is similar to patients who had valve replacement and normal controls [The increased native T1 and ECV in AS is traditionally attributed to interstitial expansion due to diffuse fibrosis. However, if T1 changes were due to interstitial expansion and diffuse fibrosis only, then we would expect an increase in T1 values in AS both at baseline and during the stress due to presence of increased interstitial water. In contrast, we found that stress T1 values were similar for control and AS patients. The complete normalization of both resting T1 and vasodilator T1 response after AVR although the percentage of LV myocardium that shows focal fibrosis is unchanged indicates a significant role of the intravascular compartment in myocardial tissue pathology in AS. This concurs with a previous study by Eberli controls .Figure The change in partial blood volume itself is hard to measure directly and is usually approximated as about a third of the corresponding change in the flow . AssuminOur findings suggest that whenever adenosine stress is part of a CMR protocol that includes T1 mapping for ECV estimation, post contrast T1 should be acquired after a sufficient time has passed to ensure that myocardium is no longer in hyperemic state. Furthermore, our findings may also have important clinical implications as T1 changes in AS may serve as a marker for determining disease progress and therapeutic response, although this should be explored further in larger studies with a wider spectrum of AS severity.Our study population was small in line with a proof of concept study, and therefore confirmation in larger scale studies is warranted. We performed a single mid-ventricular short-axis T1-map during stress, which represents a sample of the myocardium rather than the entire left ventricle; however we believe that the myocardial changes in severe AS are mostly homogenous, and this is therefore unlikely to affect the results. Although good agreement of normal resting myocardial T1 has been documented between ShMOLLI and MOLLI T1-mapping techniques , the numPatients with severe aortic stenosis demonstrated increased resting myocardial T1 values, which correlated with aortic valve area, LVH and impaired myocardial perfusion reserve, but achieved the same maximal stress T1 response as healthy controls. The abnormal resting myocardial T1 and ΔT1 stress response normalized seven months post-AVR without specific treatment towards regression of myocardial fibrosis. Our findings support the concept that the intravascular compartment is a significant contributor to myocardial T1 relaxation times, and provide a novel mechanism to explain the T1 changes previously only attributed to diffuse myocardial fibrosis in the interstitial compartment. Coronary reserve may be assessed using native T1-mapping and this may serve as an alternate biomarker for disease severity and therapeutic response in aortic stenosis.


Sphingolipid deposition in Fabry disease causes left ventricular (LV) hypertrophy, of which the accurate assessment is essential. Cardiovascular magnetic resonance (CMR) has been proposed as the gold standard. However, there is debate in the literature as to whether papillary muscles and trabeculations (P&T) should be included in LV mass (LVM).incP&T) or excluding (MexP&T) P&T, in a cohort of Fabry disease subjects (n = 20) compared to a matched control group (n = 20). Significant differences between the two measurement methods were observed for LV end-diastolic volume, LV end-systolic volume, LVM, and LV ejection fraction (LVEF) in both groups. These differences were significantly greater in the Fabry group compared to controls, except for LVEF. P&T contributed to a greater percentage of LVM in Fabry subjects than controls . In the control group, both volume-derived methods (MincP&T or MexP&T) provided accurate SV measurements compared with the internal reference of velocity-encoded aortic flow. In the Fabry group, inclusion of P&T (MincP&T) resulted in good concordance with phase contrast flow imaging .We examined the accuracy of 2 CMR methods of assessing LVM and LV volumes, including (MThe volumetric contribution of P&T in Fabry disease is markedly increased relative to healthy controls. Failure to account for this results in significant underestimation of LVM and results in misclassification of a proportion of subjects. Fabry disease is a X-linked disorder characterized by deficient activity of α-galactosidase A, which leads to progressive lysosomal accumulation of complex sphingolipids, predominantly globotriaosylceramide . In the In this study, we compare two different CMR approaches in quantifying left ventricular volumes, function and mass in a cohort of Fabry disease subjects compared to controls. We hypothesized that incorporating the P&T during measurements of LVM is of greater importance in patients with ventricular hypertrophy.Twenty subjects with known Fabry disease (genotype positive), from the New South Wales and Queensland states Fabry registry databases, who had been referred for CMR as part of clinical management were included. To avoid any influence of gender on our analysis, only male patients were included. Twenty age-matched male controls were randomly selected from a database of ‘normal’ healthy volunteers with no history of cardiac disease. The study was approved by the relevant Institutional Human Ethics Committees.MRI data was acquired using Balanced Steady-State Free Precession (bSSFP) cine imaging on a 1.5 T Tesla Signa HDxt GE system  or a 3.0 Tesla GE system . Cardiac chamber volumes and myocardial mass were quantified using a short axis stack of images acquired during end-expiratory breath hold. Phase contrast velocity encoded data was acquired in the ascending aorta at the level of the main pulmonary artery bifurcation using breath-held gradient echo flow-encoded cine images acquired with 20 phases .http://www.osirix-viewer.com) [http://www.stil.net.au/downloads). LV end-diastolic and end-systolic volumes, LV mass (LVM), LV stroke volume (SV) and LV ejection fraction (LVEF) were obtained from the short axis stack by manually contouring end-diastolic and end-systolic endocardial borders and end-diastolic epicardial borders from the base to the apex. The 4-chamber and LVLA views were used to confirm the segmentation to ensure accuracy at the base [incP&T – Papillary muscles and trabeculations with signal intensity within 1 standard deviation of the myocardial signal measured in the LV free wall were manually outlined and included in the myocardial area. Trabeculations below 1.5 mm were also not included in the segmentation [ Mentation .exP&T-–Papillary muscles and trabeculations were excluded from the myocardial area and included in the blood pool by defining the endocardial border as a continuous contour following a smooth path along the compacted myocardium, not including the distinct trabeculations and papillary muscles. MCMR images were viewed using Osirix software (wer.com) . Analysithe base . The LV exP&T approach match the LVM calculated from end-systole with the end-diastolic LVM . We chose not to perform this step, as this was felt unnecessary for the purposes of our comparison. Aortic outflow was calculated off-line and manually on a workstation .All endocardial and epicardial borders were contoured manually by both an experienced CMR Radiologist (SMG) and Cardiologist (RK). Both endocardial and epicardial borders were traced at end-diastole and only the endocardial borders at end-systole. End-diastole was defined visually as the phase with the largest intracavity volume, and end-systole as the phase with the smallest intracavity volume. The basal slice was selected when at least fifty percent of the left ventricular cavity was surrounded by myocardium at end-diastole. The apical slice was selected as the last frame showing intracavity blood pool at end-diastole. LV volumes and mass were compared between the 2 methods described above in both Fabry and control subjects. As an internal reference, SV calculated using the two methods was then compared with aortic SV measured by velocity-encoded flow sequences in the ascending aorta. Many sites that employ a MTo verify the reproducibility and reliability of the different methods, the intra-observer and inter-observer repeatability of LVEDV and LVESV measurements were assessed in half of the subjects. For intra-observer variability, the measurements were performed twice by the same observer (RK) with at least 1 week between measurements. For inter-observer variability, the first measurements from observer 1 were compared to the measurements calculated by a second independent observer (SG), who was blinded to the initial results.Statistical analyses were carried out using SPSS 21 . All continuous variables are expressed as mean ± standard error of the mean. Categorical variables are expressed as frequencies or percentages. Outcome variables were compared using paired-samples t-test for matched variables within each subject group, and independent-samples t-test for variables between the groups. A p-value of <0.05 was considered statistically significant. The Bland Altman statistical test was used to assess intra- and inter-observer variability, with the results presented graphically including mean differences and 95% limits of agreement, and the coefficient of repeatability.All participants were males. The Fabry and control groups had a mean age of 42 ± 3 vs 35 ± 1 years (p = 0.08), and range 13–66 vs 27–56 years, respectively.incP&T and MexP&T) are summarized in Table incP&T and MexP&T methods were markedly greater in the Fabry group compared to the controls for LVEDV, LVESV and LVM.The measures of LV volumes and mass obtained using the two methods (MincP&T), the difference in LVM between Fabry subjects and controls subjects was 178 ± 14 vs 130 ± 6 g (p = 0.003). This pathological difference was less evident when P&T were excluded . This proportional difference appears to be explained by the fact that the papillary muscles and trabeculations contributed to a greater percentage of cardiac mass in Fabry patients than control subjects  gave similar values to the stroke volume calculated from the velocity-encoded data (p = ns). However, in the Fabry group, exclusion of P&T (MexP&T) resulted in a significant 12% overestimation of SV compared to aortic flow technique . This was corrected by the inclusion of P&T  drawn from the Framingham study also supports the use of a Msubjects . The hiserations . Howevere images . This ise images . This teincP&T approach. This effect is driven by the increased contribution papillary muscle hypertrophy makes to overall cardiac mass in Fabry disease, versus non-deposition forms of LV hypertrophy, and has important implications for disease severity classification and therapy in this disease.In the context of cardiac hypertrophy, the effect of type of volumetric analysis approach on the estimation of cardiac mass is of even greater importance than the functional measures. In the Fabry group, papillary muscle and trabecular mass contributed to an average 20% of the total cardiac mass, over one and a half times more than that of the control group Figure . Thus, cOnly males were analysed in this study to avoid any influence of gender on hypertrophy in general. We acknowledge that this is a limitation considering Fabry disease affects both genders. It is unclear whether the results can be translated to females, given the gender differences in Fabry cardiomyopathy regarding LVH .incP&T approach in this cohort may have altered the eligibility for ERT for five of this study’s patients. Our data strongly suggest that accurate measurement of LVM is best achieved using a method that accurately defines the endocardial border so as to include all significant trabeculations and papillary muscles. This analysis deliberately focused on examining subjects with Fabry disease versus controls; further studies are required to explore if the results apply to other types of cardiac hypertrophy.The findings of our study have considerable importance in the setting of Fabry disease due to the availability of enzyme replacement therapy (ERT) and the targeting of this therapy to those with identified end-organ involvement. ERT has been available since 2001, and data over the last decade suggests that ERT has the potential to change the prognosis of Fabry disease -21. DespThe volumetric contribution of papillary muscles and trabeculations in Fabry disease is markedly increased relative to healthy controls in males. Failure to account for this results in significant underestimation of LVM and results in misclassification of a proportion of subjects. While Fabry patients represent an uncommon example of hypertrophy, they underline the importance of accurately contouring the endocardial border for quantification of left ventricular assessment.


Microvascular obstruction (MVO) after coronary reperfusion for acute myocardial infarction (AMI) implies advanced myocardial damage and is recognized as a negative prognostic value. Delayed contrast-enhanced MRI is the preferred MR imaging technique for evaluation of MVO. In this study, we assessed the influence of MVO on post-infarction left ventricular (LV) remodeling and dysfunction.92 successfully reperfused ST-segment elevation MI patients were prospectively studied. Cardiovascular magnetic resonance was performed at 2±4 days (baseline) and 6 months (follow-up) on a 3-T scanner , including cine SSFP and delayed contrast-enhanced sequences. Contrast-enhanced images were acquired 10-20 minutes after gadolinium injection . LV volumes , ejection fraction (LVEF), infarct size and MVO (defined as a dark zone within the infarcted segments) were analyzed using MASS Analytical Software . MVO and infarct size were expressed as percentage of LV mass (%LV). Adverse LV remodeling was defined as an increase in LV end-diastolic volume ≥20% at follow-up. Data from patients with MVO and those without MVO were compared. Student t-test and Fisher's exact test were used for continuous data and categorical data comparison, respectively. A level of p<0.05 was considered statistically significant.p<0.05 for all). In addition, although LVEF improved equally in two groups (p>0.05), there was a significant increase of LVEDV in MVO group . Furthermore, adverse LV remodeling, using the predefined criterion, occurred in 13 out of 57 patients with MVO and in only 2 out of 35 patients without MVO (Fisher's test: p=0.04). Besides, reduction of LVESV, likely related to the regression of stunning, was much higher in no MVO group (p<0.05).Even though successful reperfusion (TIMI flow grade 3) was achieved, MVO was still detected in 62% (57/92) patients at baseline . Comparison data were shown in Table Patients with MVO experienced more pronounced LV remodeling and dysfunction even under the condition of restoration of epicardial coronary flow. The negative prognostic value of MVO helps patient risk stratification and might be a promising surrogate endpoint to evaluate reperfusion therapy strategies.Financical support from Guerbet company.


To determine whether keeping the heart empty and beating is an effective technique to preserve hypertrophied pig hearts, and to investigate the underlying mechanism.Ten Bama Miniature pigs with hypertrophied hearts were divided into 2 groups (n = 5 in each group). One group underwent normothermic normokalemic simultaneous perfusion (NNSP). The other group was subjected to normothermic hypermokalemic simultaneous perfusion (NHSP) and used as controls. Cardiac contractive function, myocardial energy metabolism and myocardial perfusion were assessed using magnetic resonance imaging. Western blot analysis was carried out to determine the expression of Troponin I (cTnI), Troponin T (cTnT), SM-MHC, Casapase-3 and PARP4. TUNEL assay was used to detect apoptotic cardiomyocytes.2 area was significantly increased in NHSP group compared with NNSP group.Keeping the heart empty and beating with NNSP improved the preservation of contractile function in comparison with cardioplegic arrest using NHSP. No significant differences existed in the effects of NNSP and NHSP in maintaining myocardial energy metabolism. 13 % perfusion defects areas were found in one heart in the NHSP group, whereas none was found in all other hearts in both groups. The expressions of cTnI, cTnT, Casapase-3 and PARP4 in NHSP group were abundantly increased compared to NNSP group as measured by Western blotting. Conversely, the expression of SM-MHC in NHSP group was reduced compared with NNSP group. The number of TUNEL positive nuclei per mmKeeping the heart beating with NNSP is an alternative technique to preserve hypertrophied hearts during valvular surgery. It is well acknowledged that to date cardiac surgery is the most effective therapeutic treatment for valve diseases . For safMyocardial hypertrophy, accompanied with the development of perivascular and interstitial accumulation of connective tissue, directly deteriorates contractility and relaxation of the heart –11. It iSince the development of beating coronary artery bypass grafting (CABG), cardioplegia is no longer considered to be an indispensable component for cardiac surgery . WhetherAll procedures involving animals were approved by Harbin Medical University Ethics Committee for Animal Experiments and performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.Ten 8- to 10-week-old Bama Miniature Pigs weighing 10 to 15 kg were sedated with an intramuscular injection of diazepam (0.4 mg/kg body weight) and ketamine (20 mg/kg body weight). Once anesthetized, piglets were intubated and mechanically ventilated. Intravenous injection of 3 % pentobarbital sodium was given to maintain anesthesia throughout the operation. To start, a left lateral thoracotomy was performed in the third intercostal space. The pericardium was incised, and care was taken to avoid damage to the phrenic nerve. A piece of suture inside a silicone tube was then placed to circle the ascending aorta. Followed by that the ends of the suture were tied to allow for overlap of the tube ends to create a peak systolic pressure gradient of 10 to 20 mm Hg between the left ventricle (LV) and aorta distal to the stenosis. The operation finished by closing the chests and the animals were allowed to recover for 12 weeks for the development of LV hypertrophy.Twelve weeks after aortic banding, the chests were reopened under a general anesthesia. Firstly the pericardium was opened longitudinally along the midline. After animal heparinization , the aorta, pulmonary artery, and inferior and superior vena cava were dissected and clamped. Conventional cardiopulmonary bypass was established with ascending aortic and single right atrial cannulation with systemic normothermia (36.5 °C-37 °C), perfusion flow rate 250 ml/min and retrograde perfusion pressure at 80-120 mmHg. An aspirator was placed near the coronary sinus through an incision under the right atrium. The effluent was collected continuously by the aspirator.4, 0.5 mmol/L ethylenediaminetetraacetic acid, 11 mmol/L glucose, 25 mmol/L NaHCO3, 1.75 mmol/L CaCl2 and 0.625 % bovine serum albumin. The concentration of potassium was 4.0 and 16 mmol/L for normothermic normokalemic simultaneous perfusion (NNSP) and normothermic hyperkalemic simultaneous perfusion (NHSP), respectively. The temperature of the heart was maintained at 36.5 °C to 37 °C throughout the operation.Pig blood was collected from the animal chest and mixed with Krebs-Henseleit solution in a 1:1 ratio for perfusion. Krebs-Henseleit solution is widely accepted as a physiologic perfusion medium and has been used for many years for heart perfusion. The Krebs-Henseleit solution contained 118 mmol/L NaCl, 1.2 mmol/L MgSOTen hypertrophied hearts were divided into two groups with five hearts in each group. Group 1 (n = 5) were used to evaluate the effect of empty beating (NNSP). Group 2 (n = 5) were used to evaluate the effect of cardioplegic arrest (NHSP). Both groups underwent a protocol consisting of 80 min of either NNSP (group 1) or NHSP (group 2). The 80-min preservation period was chosen because it was sufficient for most valve surgeries. Intermittent delivery was used for normothermic cardioplegic arrest in this study. After the 80-min preservation period, the aortic cross clamp was removed in both groups. Normal perfusion of was given and patients core temperature stayed 35–37 °C. The sternum was subsequently closed.Cardiac contractive function and LV wall thickness were assessed using cine MRI immediately after the surgery. The total time interval was less than 20 min. Myocardial energy metabolism was monitored by using phosphorus 31 magnetic resonance spectroscopy. MR perfusion imaging was used to evaluate myocardial perfusion. All of the MRI images were collected by Philips Achieva 3.0 T superconducting MRI scanner.After imaging examination, the animals were killed, autopsied and the myocardial specimens were harvested. Both the heart and LV weight  were measured. Corresponding data of normal pig hearts, used as control for this study, was referred to another study of us which had not been published yet (data unpublished). Tissues of LV (with coronary artery) were taken for lab experiment. Western blot analysis was carried out to determine the expression of Troponin I (cTnI), Troponin T (cTnT), smooth muscle myosin heavy chain (SM-MHC), PARP4 and Casapase-3. TUNEL assay was used to detect apoptotic cardiomyocytes.Left ventricular end-systolic volume and left ventricular end-diastolic volume were measured by the cine MRI. Contractile ability of the hypertrophied hearts was also assessed by left ventricular ejection fraction [(left ventricular end-diastolic volume and left ventricular end systolic volume) / left ventricular end-diastolic volume].31P) MR spectroscopy was performed on a 3-T magnet equipped. The 31P MR spectra were acquired using a MR surface coil. Monitoring 31P MR signal intensity was performed using a point resolved spectral selection (PRESS) sequence during the test. Phosphorus compounds included phosphocreatine (PCr), inorganic phosphate (Pi) and 3 peaks  of adenosine triphosphate (ATP) were observed and noted. The β peak was used for quantifying ATP.Phosphorus 31 (n = 5) and 2 (n = 5) were subjected to the injection of Gd-DTPA . 10 min after contrast agent was injected, late enhancement was performed using a phase sensitive inversion recovery (PSIR) sequence.The blood perfusion of hypertrophy myocardial tissue was evaluated by MR perfusion imaging. Monitoring MR perfusion imaging signal intensity was performed using a echo-planer imaging (EPI) sequence. The pig hearts in groups 1  and Casapase-3 . After incubation in the primary antibody, the membrane was incubated in an appropriate secondary antibody. After washing, the bound antibody complexes were detected using an electrochemiluminescence reagent.Freshly frozen myocardial tissue samples were homogenized in RIPA buffer. Protein from myocardium tissues was extracted and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Protein2 area.Detection of apoptosis was carried out by a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labelling (TUNEL) assay (Roche Diagnostics GmbH). Approximately 20 randomly chosen, non-overlapping images covering the infarct and border regions were acquired using a × 200 objective. Blinded observers counted the number of TUNEL positive nuclei in each image. The result was then expressed as the number of TUNEL positive nuclei per mmt test (unpaired) was used to analyze the differences between NHSP and NNSP. A value of P less than 0.05 indicates significant difference.All the data collected from MRI were analyzed by using the cardiac analysis package in the post-processing workstation. All numerical results were expressed as the mean ± S.D. of the mean. Student’s P < 0.05) higher in hypertrophied hearts (0.58 ± 0.04) than in normal hearts (0.48 ± 0.03). The LV wall of the hypertrophied hearts was significantly (P < 0.05) thicker (2.02 ± 0.17 cm) than that of the normal hearts (1.24 ± 0.05 cm). These data clearly indicates that 12-week aortic banding has resulted in significant LV hypertrophy.The weight ratio of LV to entire heart was significantly /left ventricular end-diastolic volume]. As the result shown in Fig. 31P MR spectra obtained from NNSP and NHSP hearts are shown in Fig. Representative MR perfusion imaging was used to evaluate the effect of NNSP and NHSP on the blood perfusion of hypertrophy myocardial tissues. The aim of perfusion scanning is to identify ischemia areas, which are seen as perfusion defects areas by MR perfusion imaging. No ischemia areas were found in NNSP group. In the NHSP group one particular heart however was found to have 13 % perfusion defects areas, while all others in the same group appear to have none.P = 0.0027 and P = 0.0104, respectively). On the contrary, the expression of SM-MHC in NHSP group was significantly reduced compared with NNSP group (P = 0.0166).In order to explore the effect of NNSP and NHSP have on the degree of myocardial fibers protein hydrolysis and blood vessel damage, western blot analysis was carried out to determine the expression of cTnI, cTnT and SM-MHC. As shown in Fig. P = 0.0163). Additionally, PARP4 was also considered to play a pivotal role in the mediation of apoptotic cascades. Our results revealed a dramatically elevated expression level of PARP4 in the heart tissue of NHSP group in comparison to NNSP group (P = 0.0008)  increased in NHSP group (51.22 ± 5.389) as compared with NNSP group (17.40 ± 2.601).Detection and quantification of apoptosis were carried out by TUNEL assay. As shown in Fig. Cardiac surgery has been considered to be a reliable treatment to correct valve abnormalities and to alleviate the life-threatening symptoms and complications of valve diseases . MyocardResearch has shown that cardioplegia techniques cause cardiac impairment, especially ischemia-reperfusion injury . Such inThe aim of perfusion scanning is to identify ischemia areas. In this study, ischemia areas were found in one heart in the NHSP group only. This observation however is not sufficient enough to conclude the effect of NNSP and NHSP on the blood perfusion of hypertrophy myocardial tissue. Therefore, further investigation is still required to determine the effect of keeping the heart empty and beating on myocardial perfusion.McDonough and Gao WD found that ischemia reperfusion injury caused degradation of cTnI and reduction of isotonic contraction of muscle force , 29. ThecTnT is a contractile protein that is rarely found but only present when myocardial necrosis occurs . As an iAs one of the composition of contraction, the expression of SM-MHC decreases when the blood vessels were found to be damaged . As reveCardioplegia techniques and ischemia reperfusion injury has led to an increased apoptosis-regulatory proteins (Caspase-3 and PARP 4) activity. The proteins activated the apoptosis signaling pathways. So, cardioplegia techniques and ischemia reperfusion injury were considered to be the main cause of myocardial cell apoptosis , 33. TheIn this study, since histologic assessment of the hypertrophied heart was not performed. No histologic evidence of myocardial hypertrophy was provided. Its pathologic changes might be somewhat different from those of a human’s hearts. However, LV wall thickness and heart weight data indicated significant myocardial hypertrophy. Results from this study have demonstrated that keeping the heart empty and beating with normothermic normokalemic simultaneous blood perfusion improved the preservation of contractile function in comparison with cardioplegic arrest using normothermic hyperkalemic blood perfusion. The basic study was proved in protecting myocardial injury, blood vessel damage and myocardial apoptosis, keeping the heart empty and beating with normothermic normokalemic simultaneous blood perfusion has obvious advantages.Although our results suggest that keeping heart empty and beating provides better mycardial protection than traditional cardioplegia techniques, our study still suffers from some limitations. Firstly, we only used one kind of infusion solution (Krebs-Henseleit solution). With the development of cardiac surgery, various infusion solutions have been developed. Further research should be carried out to compare the effects of different infusion solutions and select an optimal one. Secondly, we only detected the level of biomarkers for myocardial injury (cTnI and cTnT) in myocardial specimens harvested after the surgery. The measurement of released biomarkers (e.g. Troponins or CKMB) from the heart during reperfusion is also an important indicator for myocardial injury. Further study should also measure the released biomarkers for cardiac injury in circulation.In summary, compared to cardioplegic arrest using NHSP, keeping the heart beating with NNSP has improved preservation for hypertrophied hearts. It is also noted that further investigation is required to determine the effects of keeping the heart empty and beating on myocardial perfusion. Keeping the heart beating with NNSP is an alternative technique to preserve hypertrophied hearts during valvular surgery.


Genetic diversity, attributable to the low fidelity of reverse transcription, recombination and mutation, is an important feature of infectious retroviruses. Under selective pressure, such as that imposed by superinfection interference, gammaretroviruses commonly adapt their envelope proteins to use alternative receptors to overcome this entry block. The first characterized koala retroviruses KoRV subgroup A (KoRV-A) were remarkable in their absence of envelope genetic variability. Once it was determined that KoRV-A was present in all koalas in US zoos, regardless of their disease status, we sought to isolate a KoRV variant whose presence correlated with neoplastic malignancies. More than a decade after the identification of KoRV-A, we isolated a second subgroup of KoRV, KoRV-B from koalas with lymphomas. The envelope proteins of KoRV-A and KoRV-B are sufficiently divergent to confer the ability to bind and employ distinct receptors for infection. We have now obtained a number of additional KoRV envelope variants. In the present studies we report these variants, and show that they differ from KoRV-A and KoRV-B envelopes in their host range and superinfection interference properties. Thus, there appears to be considerable variation among KoRVs envelope genes suggesting genetic diversity is a factor following the KoRV-A infection process. A retrovirus has been implicated in the lymphoid neoplasias that have been plaguing koalas for the last several decades ,2. In 20As KoRV-A is transitioning from an exogenous to an endogenous form, it provides an ideal model for examining the presence and constancy of the KoRV-A genome over the relatively short amount of time it has participated in the process of endogenization. Four museum koala skins from the late 19th century yielded suitable DNA for analysis by hybridization capture and next generation sequencing and provided a means of obtaining some answers to questions regarding early endogenization events . Of the The 15 tested Northeastern koalas alive from 1870–1980 were positive for presumably endogenous KoRV-A provirus [The discovery of a heterogeneous population of KoRV envelope genes found in the genomic DNA and plasma of some koalas is similar to envelope variations found among feline leukemia virus (FeLV) isolates. This suggests the possibility that KoRVs may use mechanisms similar to FeLVs to overcome superinfection blocks and broaden host tropism . In thisenv in GALV-GZAP [pKoRVB-GFP was constructed by replacing GALV ALV-GZAP  with theMus dunni tail fibroblast MDTF cells [The cells used in these studies include: 293T human embryonic kidney cells (ATCC CCL 11268), murine TF cells , human HTF cells . HT1080 TF cells . 293T-RTTF cells . All celgagpol, and a retroviral genome encoding β-galactosidase (LacZ gene) as an indicator of transduction. Viral supernatants were then passed through a 0.45 µm syringe filter and stored at −80 °C. Transduction of target cells was carried out by seeding the cells at a density of 4 × 104 cells/well in a 24-well plate for 24 h. The cells were then transduced with viral vectors pseudotyped with KoRV-A, KoRV-B, KoRV-E or KoRV-F envelopes in the presence of 10 µg/mL polybrene. Forty-eight hours post exposure to vectors, X-Gal  staining was performed and blue colonies resulting from the expression of β-galactosidase were indicative of transduced cells.Transfection of 293T cells was carried out with ProFection Calcium Phosphate Transfection kit (Promega). Retroviral particles were produced by co-transfection of a pCI-neo plasmid encoding individual KoRV envelope , an MLV The collection of koala blood and tissue samples, preparation of peripheral blood mononuclear cells (PBMCs) and plasma from blood samples, and purification of blood and tissue genomic DNA were carried out as previously described . StimulaPrimer sequences used for amplification of KoRV variants are listed in The RT-PCR assay to detect KoRV variants in koala plasma was performed using envelope specific primers of KoRV-E (P4) or KoRV-F (P5) paired with P1 primer complementary to the sequences upstream of the envelope gene of all KoRV variants. The isolation of viral RNA using QIAamp Viral RNA Mini Kit  and removal of contaminating DNA was described previously . A SuperPBMCs collected from all tested koalas in U.S. zoos produce KoRV-A. . We, andWe have previously reported the isolation and sequencing of a novel exogenous KoRV isolate designated KoRV-B genome . We usedNext, we expressed a panel of known human transporters used by other gammaretroviruses in KoRV-E resistant cells, such as MDTF. Their expression was verified by transduction of the appropriate enveloped vectors. We thereby determined that the receptor for murine amphotropic retroviruses, the inorganic phosphate transporter 2, PiT2 or SLC20A2 ,19, the KoRV-F contains a VRA region that differs from KoRV-A, B, or E. However alignment of KoRV-F to the previously identified KoRV-C envelope from Japan  and the In previous studies, in which koalas from the LA zoo were assessed, we discovered that KoRV-B was transmitted from dams but not sire to offspring . A pedigUsing KoRV-B specific primers, we also isolated a KoRV-B-like genome, which has a full LTR region similar to the originally isolated KoRV-B , partialThe genomes of KoRV-A and KoRV-B are highly conserved with variability occurring mainly in the envelope gene and in the U3 or viral promoter region of the LTR. The sequenced regions of KoRV-F genome also show variability in the U3 and receptor-binding domain of the envelope when compared to KoRV-A and KoRV-B . The sinKoRV-A is a newly endogenized retrovirus that has been resident in the koala genome for several decades to a maximum age of approximately 22,200–49,900 years ago . To dateThe absence of KoRV-E or KoRV-F in the offspring of KoRV-E or KoRV-F positive parents suggests KoRV-E and KoRV-F are not invariably vertically transmitted . KoRV-A In conclusion, in contrast to the belief held for more than a decade that KoRV-A was an invariant species of virus we have now determined that there is considerable variation in the envelope regions as well as the LTRs of KoRVs. The consequence of this variation is a genetically diverse virus population that will most likely be continuously shaped by selective pressures. The nature of KoRV-B and KoRV-E and KoRV-F variants, their relationship to malignant disease, the cellular factors that contribute to disease and the selective mechanisms leading to their predominance are questions that need to be addressed to resolve KoRV-mediated pathogenesis.


Heart failure is the leading cause of death in the United States. Our increasingly aged population will contribute to an increased incidence and prevalence of heart failure, thereby augmenting the need for mechanical circulatory devices. Here we present the first successful resection of a brain tumor in a left ventricular device- (LVAD-) dependent patient with increased intracranial pressure and address pertinent perioperative anesthetic considerations and management. Heart failure continues to be the leading cause of death in United States. It is estimated to affect >5 million Americans and 550,000 new cases are diagnosed annually . AlthougAs the number of patients with long term LVAD therapy is increasing, the anesthesiologists are faced with the task of providing care to these patients for various noncardiac surgical procedures. Anesthetic considerations and perioperative management of patients with LVAD undergoing various types of noncardiac surgery have been discussed in the literature –12. With2 saturation of 93% on room air. Her neurologic examination was otherwise intact. The neurosurgery service was consulted and recommended surgical resection of the temporal brain lesion. The perioperative planning was multidisciplinary involving neurosurgery, cardiothoracic surgery, cardiology, and the anesthesiology. Her LVAD was interrogated and settings were set at a speed of 8200 rpm, pump power of 4.7, and pulse index of 6.7. She was started on dexamethasone. Her aspirin and coumadin were withheld. On the day of the surgery, her lab values were hemoglobin of 8.8 g/dL, platelet count of 9.7 × 109/L which came up to 134,000 × 109/L after transfusion of 2 units of platelets, INR 1.6, PTT 27, and PT 19.4. She was also given 2 fresh frozen plasma (FFP) to further decrease the INR intraoperatively. The patient was transported to the operating room by the anesthesiology team and a dedicated VAD nurse.Patient was a 60-year-old female who had an implantation of a Heart Mate II LVAD for ischemic cardiomyopathy about 2 years ago. She presented with a history of persistent severe headaches associated with confusion and balance problems. Brain imaging demonstrated four different ring-enhancing lesions within the brain. The largest one was located within the right temporal lobe measuring 4.4 × 5.3 cm. There was significant mass effect and edema in the right cerebral hemisphere including uncal herniation and 8 mm of right-to-left midline shift. Her past medical history was significant for chronic obstructive pulmonary disease (COPD), myocardial infarction, arrhythmia, congestive heart failure, and hypertension. She also had several episodes of GI bleeding in the past and hence she was maintained on a lower international normalized ratio (INR) goal of 1.3–1.8. Past surgical history included insertion of LVAD, hemiarthroplasty of R hip. Pertinent medications included furosemide, potassium chloride, albuterol-ipratropium inhaler, carvedilol, warfarin, omeprazole, fluticasone-salmeterol, trazodone, aspirin 81 mg, and sildenafil. Physical examination revealed a cachectic female who was 155 cm in height and weighed only 42.3 kg. Her Glasgow Coma Scale (GCS) was 14 and was confused at times. Her vital signs on admission were as follows: heart rate of 83 beats/minute, respiratory rate of 18–20 times/minute, blood pressure of 102/69 mm Hg, and O2), invasive arterial pressure, and central venous pressure. Transesophageal echocardiography (TEE) was readily available. Her radial artery was cannulated prior to induction. The anesthesia was induced with 100 mcg of fentanyl, 40 mg of lidocaine, and 100 mg of propofol which was titrated slowly, followed by 50 mg of rocuronium to facilitate intubation with a size 7.0 endotracheal tube. The anesthesia was maintained with 0.8–1 MAC of sevoflurane in 50% FiO2 and 0.08–0.1 mcg/kg/min of remifentanil. Right internal jugular central line was placed after the induction.Intraoperative monitoring included an electrocardiogram, pulse oximetry  was maintained between 80 and 90 mm Hg most of the intraoperative period with only few occasional boluses of phenylephrine. She received 500 mL of crystalloids and 2 packs of FFP. She made 1700 mL of urine. Total duration of anesthesia was about 3 hours. At the end of the case, the patient's neuromuscular blockade was reversed with intravenous neostigmine (2 mg) and glycopyrrolate (0.4 mg) and was extubated deep with the return of spontaneous respiratory activity in order to avoid any coughing and sympathetic stimulation associated with the extubation. She was transported to cardiac intensive care unit in stable condition. She was slightly drowsy but was responding to commands and had a slight left sided weakness. Her GCS was 14. Her postoperative computed tomogram (CT) demonstrated small new intraparenchymal hemorrhages at the resection site. Her neurological exam, however, remained stable and she was kept under close observation with frequent neurological checks. Her repeat CT head was improving. Hence, she was started on heparin drip about 36 hours after the surgery. The patient tolerated the procedure very well and was discharged from the hospital on postoperative day 10 in stable condition.In order to reduce the ICP, she was gradually placed in the reverse Trendelenburg position which she tolerated well. Furosemide 10 mg was administered and she was hyperventilated to maintain PaCOThis is the first case report describing successful resection of a brain tumor in an LVAD patient.The most common neurosurgical procedure performed in LVAD patients is emergency evacuation of the intracranial hemorrhage and the outcome is usually poor. It is estimated that ICH occurs in 2.5% to 10% of patients on VAD therapy , 14. SpeIn patients scheduled for elective surgery, thorough preoperative evaluation and optimization should be done which should address any coexisting end organ dysfunction, medications, anticoagulation status, and right ventricular dysfunction. Ideally, these patients should undergo their noncardiac surgery at centers where they received their LVAD under the supervision of the entire LVAD team  , 8. The Attention must be given to electrical power needs of the device including battery back-up during transport. The care must be taken while placing the grounding pad of the electrosurgical unit so that the path of the electrical current from the unit does not go through the LVAD , 10. ManVAD control consoles continuously display the device output  which includes 4 different parameters which are as follows: pump flow in liters per minute, pump speed in RPMs, power consumption in watts, and pulsatility index (PI). As such, it provides an important parameter for the assessment and optimization of patient's hemodynamics and end organ perfusion. The Heart Mate II displays a flow based upon pump power consumption and pump rotational speed. The LVAD flow can be used as a substitute of cardiac output. However, pump flow values should be used mostly for trending any changes rather than an absolute estimate of cardiac output as there can be 15% to 20% difference between flow estimate on the display and the actual flow. Pump speed should balance adequate emptying of the left ventricle with adequate end-diastolic volume for aortic valve opening. Pump power refers to the power needed to run the motor. Typical power is 6.8 W and it is within a range of up to 25.5 W. Normally, the power will increase with speed or flow. Power that increases without an increase in speed or flow should raise suspicion for thrombus development on the rotor. The PI is a measure of the size of the flow pulse generated by the pump during the cardiac cycle. During clinical use, the PI usually ranges between 3 and 4. The PI depends on the interaction among left ventricular preload, contractility, and level of assistance from the device. A high PI indicates an increased preload, an increased ventricular contribution, or a low level of device assistance. A low PI indicates a low preload, a low ventricular contribution, a high device assistance, and inflow or outflow obstruction. In patients with first generation or pulsatile LVADs, noninvasive blood pressure measurement and pulse oximetry can be used . HoweverIntraoperative hemodynamic goals should include maintaining sufficient preload, avoiding any abrupt changes in the afterload (SVR), and maintaining RV contractility and the rate and rhythm . The twoThe reduction in the preload can happen intraoperatively secondary to surgical blood loss, increased venous capacitance due to vasodilation induced by the anesthetic agents, institution of positive-pressure ventilation, changes in positioning especially reversed Trendelenburg, and RV dysfunction. In our case even though it is a routine practice to administer mannitol for this type of surgery to achieve brain relaxation, mannitol was not used in order to avoid fluid overload and excessive diuresis later. Additionally, positive-pressure ventilation can significantly impede venous return and preload. Hence ventilator settings were adjusted to achieve slight hyperventilation without generating unnecessarily high intrathoracic pressures. Residual RV dysfunction is common in these patients and attention must be directed at obviating the risks of RV overfilling and increasing pulmonary vascular resistance (PVR)  . TEE is 2 responsiveness. Regarding arterial pressure, it is suggested  that the MAP be kept between 70 and 80 mm Hg [Anesthetic goals from the neuroanesthesia perspective involve preserving the brain from the secondary insult by taking measures to decrease ICP, avoiding hypoxemia, hypercapnia, and hypo- and hypertension, and maximize the brain elastance to decrease the effects of retractor pressure and ischemia , 20. Int80 mm Hg . MaintaiThere is no one anesthetic technique or agent that is superior to the others. Understanding the unique physiology of the devices and the pathophysiology of the underlying heart failure and intracranial process and following the hemodynamic goals that are discussed before are crucial. Anesthetic induction should be done carefully to prevent any abrupt fall in SVR and cardiac depression. It is also important to maintain adequate depth to avoid excessive sympathetic stimulation which can increase SVR and also ICP. Fall in the SVR due to anesthetic agents can contribute to hypotension and judicious vasoconstriction should be used as necessary.Thus even though anesthetizing patients with VADs can be challenging, by meticulous preparation, monitoring, and vigilance, patients with LVAD can safely undergo some of the most complex surgeries.


Subsequently a T2-prep pulse [prep is applied to generate the additional T2 weighting, after which a single shot SSFP image is acquired. The process is repeated for 13 heartbeats with various  corresponding to heartbeat k, to sample different T1-T2 weighted images. The first heartbeat is acquired with no magnetization preparation.The sequence diagram is depicted in Figure ep pulse  with ech1 and T2 maps were estimated jointly by voxel-wise least squares fitting to a 4-parameter signal model, A (1- exp(-Tsatk/T1)) exp(-TEprepk/T2) + B. Phantom imaging of 14 vials with different T1/T2 values were performed and compared to inversion-recovery and CPMG spin-echo references, respectively. Breath-held in-vivo imaging was performed on 5 healthy adult subjects, and the maps were compared to SASHA T1 maps [2 maps [The T T1 maps  and to T [2 maps .1 and T2 values not significantly different than the references (P = 0.481 and 0.479 respectively). Example in-vivo T1 and T2 maps are depicted in Figure 1 and T2 values were in good agreement .Phantom imaging resulted in T1 and T2 maps with similar accuracy and precision to saturation-based T1 mapping and to T2 mapping of same duration.The proposed sequence allows for the simultaneous estimation of accurate and jointly registered quantitative TNIH:K99HL111410-01; R01EB008743-01A2.


Vortex ring volume was unrelated to early rapid filling (E-wave) velocity in patients and controls. Characteristics of vortex-wall interaction provide unique physiologic and mechanistic information about cardiac diastolic function that may be applied to guide the design and implantation of prosthetic valves, and have potential clinical utility as therapeutic targets for tailored medicine or measures of cardiac health.The laws of fluid dynamics govern vortex ring formation and precede cardiac development by billions of years, suggesting that diastolic vortex ring formation is instrumental in defining the shape of the heart. Using novel and validated magnetic resonance imaging measurements, we show that the healthy left ventricle moves in tandem with the expanding vortex ring, indicating that cardiac form and function is epigenetically optimized to accommodate vortex ring formation for volume pumping. Healthy hearts demonstrate a strong coupling between vortex and cardiac volumes (R L/D [length/diameter], stroke ratio, or vortex formation time)21416171820212217What determines the shape of the heart? Since the early days of the universe, fluid motion conforms to the laws of fluid dynamics. These laws constitute a strong guiding force for biological evolution, and flow-function adaptations are plentiful in nature, for example the energy-saving vortex slalom of trout567810111214in vivo method for determining its three-dimensional outer boundary14To investigate the spatiotemporal behavior of the vortex ring, we have developed and validated the first We hypothesized that to optimize filling, the growth of the vortex ring is closely matched to the motion of the endocardial surface of the ventricular wall. Pathological enlargement of the heart was hypothesized to disrupt this optimized flow-function relationship between vortex and wall. Our aim was therefore to quantify the dynamics of the vortex ring boundary in relation to the left ventricular endocardium throughout diastole.in vivo demonstrated additional complexity compared to the water tank model, due to interaction with intracavitary structures such as papillary muscles , LV filling is likely to be a limiting factor for exercise tolerance. Hence the fluid dynamics of the failing heart resides closer to the limit for how large a vortex can be formed. We predict that the ratio in healthy hearts will increase during vigorous exercise, reflecting the optimized relationship between dynamic valve and flow properties and chamber size.Vortex-wall interaction may be an important consideration for the long-term performance of prosthetic valves; if the implanted valve is too small in relation to the LV or its valve leaflet orientation alters inflow direction relative to normal, it may substantially impair optimal vortex generation. Therefore, the opportunity exists for prosthetic valve implants to be tuned to the dimensions of the left ventricle in the exercise state, to ensure optimal vortex ring formation under conditions where it matters most.The narrow physiological range of vortex ring size relative to chamber size  implies From an evolutionary standpoint, matching endocardial wall movement to vortex growth implies optimization of the suction pump attribute of the LV. Because maintenance of cardiac output is a prime evolutionary directive for survival, the optimization of LV size and motion to accommodate the largest possible vortex is accompanied by numerous biological advantages. Vortex formation converts and preserves linear momentum as angular momentum13In conclusion, we have shown that the spatiotemporal behavior of the healthy left ventricle is optimized to accommodate the formation of an evolving diastolic vortex ring. Diastolic vortex ring features and dynamics are consistent across a wide size range of healthy hearts but significantly disturbed in heart failure, which increases our understanding of how fluid dynamics is coupled to, and governs cardiac shape and function. Vortex ring parameters carry implications for exercise physiology, cardiac surgery and design and implantation of prosthetic valves. Future studies should investigate vortex ring dynamics during exercise, and examine the clinical utility of vortex ring-derived metrics. The vortex ring behavior of the right ventricle also merits further characterization1624The study was approved by the Regional Ethical Review Board in Lund, Sweden, and was performed in accordance with the Helsinki declaration. All subjects provided written informed consent. Imaging and population data are available upon written request to the communicating author.16 healthy volunteers  and 23 patients  were enrolled in the study see . ControlAll subjects underwent CMR imaging using a 1.5 T Philips Achieva  or a 3T Philips Achieva , with a standardized protocol including functional imaging, and three-dimensional, three-component, time-resolved phase contrast (4D PC-MR) flow imaging. Patients additionally underwent late gadolinium enhancement imaging for infarct quantification.E/TR 1.4/2.8 ms and α 60° (1.5 T) or TE/TR 1.8/3.7 ms and α 45° (3 T), in-plane spatial resolution 1.3 × 1.3 mm, slice thickness 8 mm, no interslice gap, and acquired temporal resolution 30 ms.We acquired balanced steady-state free precession (bSSFP) cine images in 2-chamber, 3-chamber, 4-chamber and short-axis views. Typical imaging parameters for bSSFP imaging at were: TE/TR 3.1–3.7/5.1–6.3 ms and α 8°, SENSE factor 2, spatial resolution 3 mm isotropic, segmentation factor 2, acquired temporal resolution 50 ms, and retrospective reconstruction to 40 timephases. We used a navigator pre-pulse for respiratory gating in 13 controls. 3 controls and all patients were scanned during free breathing.We also acquired validated 4D PC-MR flow images from a box covering the entire heart37Late gadolinium enhancement imaging was performed on all patients to determine infarct size. We used a validated protocol in current clinical use, consisting of ECG-triggered 2D phase sensitive inversion recovery and 3D inversion recovery gradient echo experiments. Images were acquired 10–20 minutes after intravenous administration of 0.2 mmol/kg gadolinium-based contrast agent . Inversion time was chosen for best nulling of the myocardium. Infarct size was measured using the Segment Weighted automatic method with manual corrections where necessary, and calculated as infarct % of total myocardial massImages were analyzed using a plugin for Segment 1.9 th percentile of FTLE values in the images in each time phase, and lines with FTLE values >50% of this value were considered as LCS. In cases where LCS ended blindly, delineations were connected with a straight line to the next available LCS in the vortex ring.Time-resolved LCS were computed from 4DPC data in long-axis and short-axis views as previously described in greater detailLeft ventricular volumes were determined manual delineation of the endocardial border in short-axis bSSFP images. LCS were manually delineated in the short-axis view for each timeframe in diastole and were then imported and superimposed onto the bSSFP images. In cases where the LCS grew across the endocardium (due to image noise or intravoxel dephasing), LCS delineations were cropped to the endocardial delineations. The volume for each slice was calculated as the delineated area multiplied with the slice thickness. Slice volumes were then summed to produce a total LV and vortex ring volume for each timeframe.To achieve a reproducible and robust measure of the average distance between endocardium and LCS, we took the following steps for each point in time: first, find the radius of a sphere whose volume is equal to the LV volume; second, find the radius of a sphere with a volume equal to the volume inside the LCS delineations; third, subtract the LCS sphere radius from the LV sphere radius.To investigate the relationship between mitral valve dimensions and vortex ring size, we took the following steps: first, we reconstructed through-plane (2D) velocity maps for each slice in the short-axis view using the 4D data. Second, a region of interest (ROI) was drawn around mitral valve flow in the 2D velocity map. Mitral annular area was measured in the timeframe with peak flow, in the slice with the smallest flow profile area . We thenTo assess diastolic function in patients, we used: E/A, E/E′, mean E′, peak left atrial volume normalized to BSA, mitral E-wave deceleration time (MDT), E-wave peak velocity, and pulmonary venous flow profile, using normal values as referencedWe used GraphPad Prism 6  for all statistical analysis. Population demographics were compared using the Mann-Whitney-Wilcoxon test, with statistical significance assigned at p < 0.05. Linear correlation analysis was performed to investigate vortex and physiological parameters. For How to cite this article: Arvidsson, P. M. et al. Vortex ring behavior provides the epigenetic blueprint for the human heart. Sci. Rep.6, 22021; doi: 10.1038/srep22021 (2016).


Rupture of the free wall of the left ventricle occurs in approximately 4% of patients with infarcts and accounts for approximately 20% of the total mortality of patients with myocardial infractions. Relatively few cases are diagnosed before death. Several distinct clinical forms of ventricular free wall rupture have been identified. Sudden rupture with massive hemorrhage into the pericardium is the most common form; in a third of the cases, the course is subacute with slow and sometimes repetitive hemorrhage into the pericardial cavity. Left ventricular pseudoaneurysms generally occur as a consequence of left ventricular free wall rupture covered by a portion of pericardium, in contrast to a true aneurysm, which is formed of myocardial tissue. Here, we report a case of contained left ventricular free wall rupture following myocardial infarction. Rupture of the free wall of the left ventricle occurs in approximately 4% of patients with myocardial infarction (MI) and accounts for approximately 20% of mortality of these patients , 2. PremAn 80-year-old retired female resident of a home for the aged was admitted with recent complaints of dyspnea, dizziness, and a falling episode with a possible loss of consciousness. Her personal history revealed mild dementia, Parkinson's disease treated with carbidopa and levodopa, hypertension treated by nifedipine, and dyslipidemia treated by statins. Additional medications included acetylsalicylic acid (100 mg qd), calcium supplements, and brotizolam as a sleep inducer. The patient did not take any other medication or vitamin supplements. At admission to the Emergency Department, the patient's respiratory rate was 16 breaths/min, blood pressure was 96/60 mm Hg, heart rate was regular at 100/min, room-air oxygen saturation was 92% and temperature was 36.7°C. Physical examination revealed no apparent distress, pale 80-year-old Caucasian female, good breath sounds bilaterally, heart sounds were regular and distant, abdomen was nontender, no organomegaly was observed, and pulses were palpated as normal in the radial and femoral points of examination. A 12-lead electrocardiogram obtained in supine posture showed an axis of 5 degrees with pathological Q waves in leads V4–V6, ST-segment elevation in leads V1–V3, and T wave inversion in V1–V6 and in leads I and AVL . CardiacAt this point, it was evident that the patient had a contained left ventricular free wall rupture following myocardial infarction. Following a detailed explantation of the treatment options to the patient and her family, a noninvasive/nonsurgical treatment modality was chosen. Combined pharmacological therapy including acetylsalicylic acid (aspirin 100 mg), ACE inhibitor (ramipril 5 mg), diuretic (lasix 40 mg), and beta blocker (carvedilol 6.25 mg × 2) improved the patient's hemodynamic status and reduced the symptoms of heart failure (mostly dyspnea), additional treatment included a statin (simvastatin 20 mg), and a benzodiazepine for sleeping (britazolam 0.25 mg). After six days of hospitalization, the patient was discharged for ambulatory followup. Approximately two months following discharge, the patient was admitted with exacerbation of the heart failure complaints. Echocardiography demonstrated no change in the aneurysm or the ventricular function. Following an increase in the dose of the diuretics and stabilization of the symptoms, home oxygen was arranged and the patient was discharged.Ventricular free wall rupture occurs up to ten times more frequently than septal or papillary muscle rupture . It progMost ventricular ruptures occur within the first week after MI, approximately 50% within the initial four days; however, some cases have been reported as late as one month or even later. Acute LVFWR may present by chest pain, or by the classic features of cardiac tamponade, namely, shock with hypotension, pulsus paradoxus, elevated venous pressure, quiet heart sounds, sinus bradycardia, or frank electromechanical dissociation. Death usually ensues in a matter of minutes to hours. Cardiopulmonary resuscitation maneuvers are uniformly unsuccessful in these cases. In the subacute form, the presentation may evolve over hours, days, or even longer. This form usually presents mainly with pericardial effusion signs and symptoms and may present with dysrhythmias, syncope, prolonged or recurrent chest pain , and heart failure . In thisOpinions differ as to the most common site of the left ventricular rupture. It was suggested that a lateral wall infarction is more likely to rupture than an anterior or inferior infarction. However, anterior MIs are more frequent than lateral MIs and thus the anterior wall is the most common site. Another possible explanation for the greater prevalence of posterior subacute ruptures is that ruptures of the anterior wall cannot be tolerated, as they are rarely compressed by an adherent pericardium. The inflammatory reaction of the posterior pericardium might result in pericardial adhesions and formation of a posterior left ventricular pseudoaneurysm.Electrocardiographic findings in LV rupture patients may be related to its type and severity. Electromechanical dissociation and bradycardia are features of the acute variety, while new ST elevation (“saddle shaped”) in the affected leads or persistent noninversion of T waves may suggest the less noisy “stuttering” type of rupture.Echocardiography  is usually the preferred imaging test when LVFWR is suspected and is considered highly accurate. Color flow imaging and pulsed Doppler may be useful in the assessment of flow characteristics at the presumed rupture site, and an intravenous echocardiographic contrast agent may be useful in identifying intrapericardial hemorrhage caused by myocardial rupture or the development of ventricular pseudoaneurysm. The most common finding is pericardial effusion and its absence excludes the diagnosis of ventricular rupture.Recent evidence indicates that cardiac magnetic resonance imaging (MRI), especially with contrast enhancement, is emerging as a valuable diagnostic tool providing visualization of the entire heart and clear differentiation of structures such as the pericardium, myocardium, thrombus, and epicardial fat , 10. CleMultidetector computed tomography has also been shown to be effective in detecting LVFWR and may assist in the diagnosis , 12, espEarly diagnosis is imperative in these cases as many ventricular ruptures may be surgically corrected with a good long-term outcome. Although it is a generally acceptable that surgery provides the only definitive treatment of subacute LVFWR , cases oThe overall hospital mortality in patients with and without surgery was reported to be approximately 60% . SurgeryIn conclusion, it remains clear that despite the significant risk, surgery is the cornerstone treatment of subacute LVFWR. Nevertheless, nonsurgical management may be considered for carefully selected patients, especially for those at high surgical risk. We believe it is imperative for physicians in various specialties to be well acquainted with this entity to be able to consider it in the differential diagnosis while there is still time to save these patients' lives.