The 22q11.2 microdeletion syndrome (22q11.2 deletion syndrome -22q11.2DS) refers to congenital abnormalities, including primarily heart defects and facial dysmorphy, thymic hypoplasia, cleft palate and hypocalcaemia. Microdeletion within chromosomal region 22q11.2 constitutes the molecular basis of this syndrome. The 22q11.2 microdeletion syndrome occurs in 1/4000 births. The aim of this study was to determine the frequency of 22q11.2 microdeletion in 87 children suffering from a congenital heart defect  coexisting with at least one additional 22q11.2DS feature and to carry out 22q11.2 microdeletion testing of the deleted children's parents. We also attempted to identify the most frequent heart defects in both groups and phenotypic traits of patients with microdeletion to determine selection criteria for at risk patients.in situ hybridization (FISH) on metaphase chromosomes and interphase nuclei isolated from venous peripheral blood cultures. A molecular probe (Tuple) specific to the HIRA  region at 22q11 was used for the hybridisation.The analysis of microdeletions was conducted using fluorescence de novo.Microdeletions of 22q11.2 region were detected in 13 children with a congenital heart defect (14.94% of the examined group). Microdeletion of 22q11.2 occurred in 20% and 11.54% of the conotruncal and non-conotruncal groups respectively. Tetralogy of Fallot was the most frequent heart defect in the first group of children with 22q11.2 microdeletion, while ventricular septal defect and atrial septal defect/ventricular septal defect were most frequent in the second group. The microdeletion was also detected in one of the parents of the deleted child (6.25%) without congenital heart defect, but with slight dysmorphism. In the remaining children, 22q11.2 microdeletion originated Patients with 22q11.2DS exhibit wide spectrum of phenotypic characteristics, ranging from discreet to quite strong. The deletion was inherited by one child. Our study suggests that screening for 22q11.2 microdeletion should be performed in children with conotruncal and non-conotruncal heart defects and with at least one typical feature of 22q11.2DS as well as in the deleted children's parents. The syndrome of 22q11.2 microdeletions comprises a set of developmental abnormalities, including primarily heart and craniofacial congenital defects. The syndrome is characterised by various phenotypic changes described earlier in DiGeorge, Takao and Shprintzen syndromes. It is the most common microdeletion in the population (1/4000 births) [cardiac defect, A - abnormal face, T - thymic hypoplasia, C - cleft palate, H -hypocalcaemia [In 1993, nosological entities caused by microdeletions in this region were given a common name of CATCH 22, which is an acronym formed by the first letters of the phenotypic traits accompanying this syndrome: C - alcaemia . DysmorpApproximately 180 signs of the 22q11.2DS have been described to date. These include abnormalities of the urinary-reproductive, skeletal, gastrointestinal, nervous and immunological systems as well as psychiatric disturbances. Moreover, considerable changes in the phenotype expression are observed in persons with a deletion of the same size, belonging to the same family or even in monozygotic twins . In the DGCR6, PRODH, IDD, TUPLE1, UFDL1, TBX1, ZNF74, CRKL, whereas microdeletion of 1.5 Mbp including 24 genes has been found in 8% of patients. A minimal DiGeorge critical region (MDGCR) covers about 0.5 Mbp and several genes: CTP, CLTD, TUPLE1, UFD1, TBX1, CDC45 [In 90% of patients, the identified microdeletion covers the region of 3 Mbp, encoding 30 genes, referred to as the typically deleted region (TDR), e.g. 1, CDC45 . Atypicade novo but is also found in one of the parents who was not earlier identified as the mutation carrier [The 22q11.2 microdeletion accounts for 5% of all heart defects in newborns [ carrier . A pheno carrier .The aim of this study was to determine the frequency of the 22q11.2 microdeletion in (i) 87 children with a congenital heart defect  and at least one additional 22q11.2DS feature, (ii) a group of the deleted children's parents. We also attempted to establish the correlation of the most frequent heart defects in both groups and characteristic phenotype in patients with 22q11.2 microdeletion to determine selection criteria for at risk patients.in situ hybridization) method was used in a group of 87 children with a congenital heart defect at least one additional 22q11.2DS feature: facial dysmorphy, thymic or parathyroid gland hypoplasia or aplasia, cleft palate or lip and hypocalcaemia during the neonatal period or accompanying abnormalities of urinary-reproductive, skeletal, gastrointestinal or nervous systems. The patients were divided into two groups: with conotruncal (n = 35) and non-conotruncal heart defects (n = 52). The examined group comprised 39 girls and 48 boys. The average age of all examined children was 2 years (0-6 years); thirty one patients (35.63%) were newborns.FISH , phosphate  and ionized calcium . Low calcium levels in the blood indicated hypocalcaemia .in situ hybridization using DiGeorge (Tuple) Region Probe Dual Colour (Qbiogene) was performed according to the procedure established by the manufacturer. This probe is specific to the HIRA  region at 22q11. The hybridization signals were documented with a Zeiss-Axiophot fluorescent microscope and analysed with CytoVision 3.52 software.Heparinised lymphocytes of venous peripheral blood (0.5-1 ml each) stimulated with phytohemagglutinin were used for the cytogenetic studies. Isolated cells were grown and harvested in accordance with standard procedures. The obtained chromosome preparations were stained with the GTG standard method . FluoresThe study was approved by the Ethic Committee at the Poznan University of Medical Sciences.Microdeletions in the region q11.2 of the 22 chromosome were identified in the group of fourteen patients - thirteen children with a congenital heart defect  and at least one additional trait from the 22q11.2DS spectrum  and one parent of a deleted child. Patients were classified into 2 groups based on the conotruncal and non-conotruncal cardiac defects. Microdeletion of 22q11.2 occurred in 20% and 11.54% of the first  and the second group of children  respectively. The congenital heart defects and details of phenotypic abnormalities are described in Table The analysed group of patients with the microdeletion comprised nine girls and four boys. The mean age on the day of examination was one year and two months, with seven patients diagnosed in the first month, three - in the first year and the remaining patients in the second, third and sixth year of life. The performed karyotype analysis of all patients did not reveal any abnormalities regarding the number and structure of chromosomes.de novo.Microdeletion of 22q11.2 was detected in 1/17 parents of nine children. The parent with microdeletion did not have any diagnosed heart defects and exhibited only slight dysmorphism- ear dysplasia and arachnodactyly. The above-mentioned features were more pronounced in his child. Microdeletion was not detected in any other parent, which indicates that in the case of 7 children 22q11.2 microdeletion originated Pedigree analysis of all the patients revealed the family history with a congenital heart defect in 14 cases (16.09%). Parents of the deleted children did not harbour any congenital defects including heart or other principal trait characteristics for the 22q11.2DS.Microdeletion of 22q11.2 was detected in 14.94% of the examined patients  in deleted patients amounts to 75 and abnormal development is observed in approximately 35-40% of patients with microdeletion . Most frDiagnosis based on a clinical picture exclusively may be difficult due to the fact that 22q11.2 microdeletion phenotype is not always fully developed, dysmorphy may vary from very pronounced to quite discreet and patients may show non-typical signs. Our studies indicate that it is necessary to perform the analysis of the 22q11.2 microdeletion not only in children with congenital heart defect secondary to conotruncal heart defect but also in patients with other heart defects coexisting with at least one feature from the 22q11.2DS spectrum.Literature data reveal that about 10-20% of patients inherit 22q11.2 microdeletion from one of the parents . Frequende novo might suggest considerable genomic instability in this region of chromosome 22. The genetic mechanism behind the microdeletion is based on nonallelic homologous recombination (NAHR). The same aetiology has been observed in the case of other microdeletions - Angelman (15q11-q13 microdeletion), Prader-Willi (15q11-q13 microdeletion) and Williams-Beuren (7q11.2 microdeletion) syndromes [The high frequency of 22q11.2 microdeletions originating locus comprises approximately 30 genes. Comprehensive functional studies on animal models revealed that TBX1 is the only gene with haploinsufficiency that results in the occurrence of a phenotype characteristic for the 22q11.2DS [TBX1 gene encodes phylogenetically conservative transcription factor which takes part in the regulation of developmental processes. The extensive mechanisms in which it is involved create many possible ways for the development of abnormalities caused by haploinsufficiency - lack, excess or incorrect structure of the TBX1 gene. The discovery of the mutation in the TBX1 gene in a patient with the microdeletion phenotype and the recognition of its impact on the TBX1 protein accelerated the understanding of the molecular basis of 22q11.2 microdeletion syndrome [It is believed that some of the patients with the 22q11.2DS phenotype do not have a chromosomal microdeletion but that they are likely to be carriers of mutations in one or more genes . This fa2q11.2DS . TBX1 gehigh resolution comparative genomic hybridization (HR-CGH), multiplex ligation-dependent probe amplification (MLPA), short tandem repeats (STR) as well as quantitative polymerase chain reaction (qPCR). These methods enable researchers to estimate the size of microdeletions, determine chromosomal breakpoints and perform segregation analysis [It is possible to diagnose the 22q11.2 microdeletion using other diagnostic methods than FISH, ie. analysis .Regardless of the methods applied to diagnose 22q11.2DS, early diagnosis is crucial. This is why the possibility of prenatal identification of congenital heart defects begins to play an important role. The result of echocardiographic examinations confirming a heart defect in the foetus can frequently give the baby a chance to survive as adequate care can be provided. In addition, the result could qualify newborns to a risk group and indicate the need to perform genetic analysis. This assumption was confirmed by investigations carried out by Moore et al. who prenatally diagnosed foetuses by means of USG. They demonstrated that 41% of foetuses with congenital heart defect had an incorrect karyotype and 3% had 22q11.2 microdeletion [Long-term studies carried out in several research centres indicate that children with congenital heart defects are most likely to undergo examinations for microdeletions on chromosome 22 while being the patients on paediatric cardiology wards, even though they are under the care of other specialists . Our stuThere is a wide spectrum of phenotypic characteristics that occur in patients with the 22q11.2DS. This syndrome is characterized by a highly variable expression of phenotype, ranging from discreet to quite strong. ToF was the most frequent conotruncal heart defect in the group of children with 22q11.2 microdeletion, while ASDII+VSD and VSD were the most common in the non-conotruncal group. Our studies indicate that patients with moderate heart defects  or frequently observed complete absence of dysmorphism exhibit a typical but rare thymic hypoplasia. In one familial case of the 22q11.2DS, no cardio-vascular defect was identified in the parent who was the microdeletion carrier, despite the fact that tetralogy of Fallot was diagnosed in the child with the same mutation.Many patients with the 22q11.2DS additionally suffer from accompanying defects, primarily, associated with urinary-reproductive, skeletal, gastrointestinal, nervous systems and the organ of sight. Therefore, at various stages of life they will require multi- and highly-specialized care of cardiologists, cardiosurgeons, immunologists, orthopaedists, psychologists and psychiatrists. Such long-term and specialized care over patients with the 22q11.2DS is provided, for example, in Goteborg, Tokyo or Philadelphia . It shouThe authors declare that they have no competing interests.Being the principal investigator of the project, AW planned and organized the study, conducted FISH analysis and prepared the manuscript, DW-B, MW, RG, AM-K, TM, MB-S, MK enlisted the patients and provided clinical data. JS, JZ performed FISH. AL-B, AS, WB, RS verified and interpreted clinical and genetic results.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/10/88/prepub


Aim of the Study. To evaluate diagnostic usefulness of cTnT in correlation with other markers of circulatory failure and myocardial damage in newborns with heart defects. Patients and Methods. The study involved 83 newborns up to 46 weeks of postmenstrual age. The exclusion criteria were severe perinatal asphyxia and presence of severe noncardiac diseases. Patients were divided into 2 main groups: group I—54 patients with congenital heart defects (CHDs), and group II (control)—29 healthy neonates. All patients underwent detailed examination of circulatory system. Cardiac troponin T (cTnT) concentrations were evaluated by Roche CARDIAC T Quantitive test. Results. Performed studies revealed that cTnT levels in newborns with heart pathology were significantly higher than in healthy ones. However, cTnT concentrations in patients with CHD did not correlate with clinical symptoms of heart failure, nor with echocardiographic markers of LV function. Type of heart defect did not influence cTnT levels as well. Only hemodynamic significance evaluated by echocardiography influenced the cTnT levels with statistical significance. Conclusions. (1) Statistically significant differences in cTnT levels between newborns with heart defects and healthy subjects were shown. (2) CTnT levels in newborns with heart defects refer only to hemodynamic significance of the defect.Heart diseases are a significant cause of morbidity and mortality in newborns. Diagnostic methods are often not sufficient or, in many cases, cannot be used. There is a great advance in medical knowledge concerning biomarkers in the diagnosis of circulatory system in adult patients. Among them, cardiac troponins play the main role. In current literature, there is not enough data concerning the possibility of using them in neonatal cardiac diagnostics.  Heart diseases leading to circulatory failure are a significant cause of morbidity and mortality in newborns . DiagnosCardiac troponins are protein components of the tropnin-tropomyosin complex in myocardium. Since troponins do not occur in extracellular space, their appearance in serum is sensitive and specific marker of myocardium damage . TroponiSensitivity of both cTnT and cTnI in the diagnosis of myocardial damage is clinically almost equal. They differ in intracellular compartments, biological half-life, and molecular weight . There aCardiac troponins (cTn) are biochemical markers of myocardial injury with unquestionable significance in diagnostic strategy in adults , 7–11. HWas to evaluate the diagnostic usefulness of cTnT measurements in correlation with other markers of circulatory failure and myocardial damage in newborns with congenital heart defects.The study involved 83 newborns up to 46 weeks of postmenstrual age. The gestational age of studied newborns was 25–42 weeks, mean: 38 weeks. Chronological age (in days from the date of birth) was 6–135 days, mean: 21 days. Postmenstrual age was 34–46 weeks, mean: 41 weeks. Birth weight of studied newborns was 585–5400 g, mean: 3137 g. The exclusion criteria were severe perinatal asphyxia  and patients with signs of severe noncardiac diseases.All patients underwent detailed subjective and physical examination. In patients with abnormalities in circulatory system echocardiography and electrocardiographic tests were performed. On the basis of performed examination, patients were divided into 2 main groups: group I—54 patients with congenital heart defects (CHDs), and group II (control)—29 healthy neonates up to 46 weeks of postmenstrual age. Newborns with CHD were divided into following subgroups: group Ia—with simple shunts and group Ib—with combined heart defects . PatientEach newborn with cardiac abnormality had the following examinations performed: echocardiography with left ventricle ejection fraction (EF LV) evaluation, chest X-ray, and blood pressure measurement. All patients were also evaluated with Ross'es heart failure in infants classification  and withT levels were evaluated in 150 μL of whole blood by Roche CARDIAC T Quantitative test . The Roche CARDIAC T quantitive test includes two monoclonal antibodies specific for cardiac troponin T. Measuring range of the test is 0.03 to 2 ng/mL. The results are not influenced by hyperbilirubinemia (bilirubin <20 mg/dL), hemolysis nor lipemia (triglicerydes <440 mg/dL). Blood samples were collected into standardized heparinized tubes. The obtained results, after checking the normality of distribution, were statistically analyzed by the use of appropriate test with Statistica 9.0 packet. Right-handed asymmetry of certain distributions was eliminated by the use of logarithmic transformation. Dependency analysis was performed based on Pearson's linear correlation coefficient (r) or Spearman's (R) rank correlation test and t-test significance of the correlation coefficient in the population. The results were concerned as statistically significant when P < 0.05.Troponin P = 0.035, R = 0.095 and P = 0.493) as well as with Reithmann's classification . Cardiac TnT concentrations also did not correlate with echocardiographic markers of LV function, nor with the type of heart defect. The obtained results revealed that only hemodynamic significance of heart defect evaluated by echocardiography influenced the cTnT levels with statistical significance  evaluated by echocardiography and cTnT concentration in newborns with CHD was observed. The above result is difficult to be referred with data from the literature, as yet only one study led by EL-Khuffash et al.  showed cStructural heart defects are the most often inborn malformations diagnosed in the first year of life . StudiesStealing of oxygenated blood by arterial duct can influence the coronary flow, and potentially lead to ischemia [On the basis of our studies, it was found that cTnT serum concentration is statistically significantly higher in newborns with CHD compared to patients from the control group. In available literature, it is difficult to find studies concerning troponin concentrations in neonatal patients with heart defects. One of the papers  showed tischemia .In another research, conducted by EL-Khuffash et al.  on groupIn available literature, there were no other studies found concerning cardiac troponin concentrations in CHD in newborns before cardiosurgeric treatment. In our previous study, cTnI concentrations were evaluated in 41 newborns at the age of 7–28 days with CHD [The results of our study confirmed that although cTnT concentrations are significantly higher in newborns with CHD compared to healthy ones, however, no significant difference was found depending on the type of the defect. In newborns with isolated left-to-right shunt defects, no significant correlation was observed between cTnT concentration and shunt velocity evaluated by echocardiography. Also, no significant correlation was found between cTnT concentration and the diameter of septal defect or PDA. However, the obtained results showed significant correlation between cTnT concentration and hemodynamic significance of heart defect evaluated on the basis of echocardiographic evaluation. Heart defects more hemodynamically significant carry greater risk of heart failure development and necessity to start appropriate treatment as soon as possible. The correlation between cTnT concentration and hemodynamic significance of CHD creates potential possibility for above biomarker to be used for early detection of newborns with significant heart defects, who need urgent cardiology consultation.Statistically significant differences in cTnT levels between newborns with heart defects and healthy subjects were shown.Cardiac TnT concentrations in newborns with CHD does nor correlate with clinical signs of heart failure nor with echocardigraphic markers of LV function.Cardiac TnT concentrations in newborns with CHD does not depend on the type of the defect.The statistically significant correlation was found between cTnT concentration and hemodynamic significance of CHD in examined newborns.


To investigate the therapeutic effects of renal denervation (RD) on post- myocardial infarction (MI) cardiac remodeling in rats, the most optimal time for intervention and the sustainability of these effects.One hundred SPF male Wistar rats were randomly assigned to N group , MI group,RD group , RD3+MI , MI1+RD , MI7+RD . MI was produced through thoracotomic ligation of the anterior descending artery. RD was performed through laparotomic stripping of the renal arteriovenous adventitial sympathetic nerve. Left ventricular function, hemodynamics, plasma BNP, urine volume, urine sodium excretion and other indicators were measured four weeks after MI.(1) The left ventricular function of the MI group significantly declined (EF<40%), plasma BNP was elevated, urine output was significantly reduced, and 24-hour urine sodium excretion was significantly reduced. (2) Denervation can be achieved by surgically stripping the arteriovenous adventitia, approximately 3 mm from the abdominal aorta. (3) In rats with RD3+MI, MI1+RD and MI7+RD, compared with MI rats respectively, the LVEF was significantly improved , hemodynamic indicators were significantly improved, plasma BNP was significantly decreased, and the urine output was significantly increased . However, the urinary sodium excretion also increased but without significant difference.RD has preventive and therapeutic effects on post-MI cardiac remodeling.These effects can be sustained for at least four weeks, but there were no significant differences between denervation procedures performed at different times in the course of illness. Cardiac function, hemodynamics, urine volume and urine sodium excretion in normal rats were not affected by RD. Acute coronary occlusion results in the loss of myocardial tissue, the inhibition of myocardial function, and low blood pressure. This leads to the activation of a series of neurohormonal factors, such as the baroreceptor-mediated sympathetic nervous system, the renin-angiotensin-aldosterone system (RAAS), endothelin, and tumor necrosis factor, which increases the heart rate, myocardial contractility, vasoconstriction, and fluid retention to help maintain hemodynamic stability. However, in this case, these intended mechanisms for short-term maintenance of blood pressure caused sustained activation, and will lead to left ventricular remodeling and deterioration of left ventricular function. Of these mechanisms, the chronic activation of the sympathetic nervous system is the main mechanism of post-MI heart failure. In recent years, some clinical trials have demonstrated that RD has improved sodium and water retention and the chronic over-activation of the sympathetic nervous system, achieving a breakthrough in the treatment of refractory hypertension. In 2002, Nozawa et al. explored the role of RD in heart failure, and their study proved that RD improves left ventricular remodeling and function, and increases water and sodium excretion. In the present study, we used six groups of rats: RD3+MI, MI1+RD, MI7+RD, MI, RD, and Normal. After four weeks of observation, body weight, left ventricular weight, left ventricular function, hemodynamics, plasma BNP, urine volume, urine sodium, and other indicators were measured. By comparing the use of RD treatment at different times in the course of illness, we were able to find the most optimal time to use RD in post-MI cardiac remodeling and confirm experimental evidence of the sustainability of RD.The experiment scheme and the use of rats were approved by animal use and management ethics committee of the First Affiliated Hospital of Xinjiang Medical University (batch: IACUC-20110325017). Experimental design and the implementation process were undertaken in accordance with animal welfare guidelines, 3 R principles, and AAALAC  standards.One hundred male Wistar rats  were obtained from the Experimental Animal Center of Xinjiang Medical University. These rats were housed in groups at a temperature of 22–25°C in a 50 to 70% humidity controlled room with a 12-hour light/dark cycle. A standard rat diet containing 0.3% NaCl and tap water were given ad libitum throughout the experimental period.The rats were randomly assigned to six groups , i.e., MI group (simple MI) n = 20, RD group  n = 10, N group  n = 10, RD3+MI  n = 20, MI1+RD  n = 20, MI7+RD  n = 20.MI was induced by ligation of the left coronary artery under combined intraperitoneal anesthesia (Ketamine (75 mg/kg), diazepam (5 mg/kg), atropine (0.05 mg/kg)). Endotracheal intubation was followed by mechanical ventilation. A left thoracotomy was performed to exteriorize the heart. The left anterior descending coronary artery was ligated together with a small amount of myocardial tissue approximately 2–3 mm from its origin with a 7–0 silk suture. Hallmarks of success for the white surface of the heart, the heart beat decreased and ECG T-wave changes occurred. Intraperitoneal injection of 1% lidocaine (1 mg/kg) was given if ventricular fibrillation occurred. The thorax was closed, and after cardiopulmonary resuscitation and restoration of spontaneous breathing, rats were placed in 28°C environment. Half an hour later ECG  was retested; ST segment elevation was recognized as a successful model. After rats were awoken, they were given daily pethidine 50 mg and penicillin 200,000 U intramuscularly for 3 days. Infarct size of >30% was deemed as successful in this model.Bilateral RD was performed under intraperitoneal anesthesia (Ketamine (75 mg/kg), diazepam (5 mg/kg), atropine (0.05 mg/kg)). Bilateral flank incisions were made, and RD was performed surgically by stripping the adventitia of renal arteries and veins at about 3 mm from the abdominal aorta for 1–2 cm and dissecting all visible renal nerve bundles, and coating the vessels with a solution of 10% phenol in ethanol. We evaluated the effects of RD by electrically stimulating  the renal sympathetic nerve at the proximal renal artery for 10–30 s before and after renal denervation, respectively, to observe the disappearance of sympathetic effects. In normal rats, electrical stimulation can cause the blood pressure to increase 5–10 mm Hg, the heart rate to increase 8–15 bpm, and the kidney to become paler in color. When electrically stimulated after RD, sympathetic effects were absent with no apparent changes in heart rate, blood pressure, or color of the kidney.The rats were moved to individual metabolic cages with free access to tap water. Urine was collected for 24 h. After the measurement of urinary volume, the rats were returned to the original cage. Urine sodium concentration was measured by electrolyte analyzer IMS-972Plus , using the ion-selective electrode method.Four weeks after MI induction, transthoracic echocardiography was performed under ether anesthesia with a high-resolution small animal echocardiographic system equipped with a Heart RMV710 probe . A two-dimensional short-axis view of the left ventricle (LV) was obtained at the level of the papillary muscle and two-dimensional targeted M-mode tracings were recorded. End-diastolic and end-systolic LV internal dimensions and fractional shortening and ejection fraction were determined from at least three consecutive cardiac cycles.Max and dP/dtMin) were obtained from the signal processing computer system of the multichannel electrophysiology instrument.After echocardiographic data collection, a 2-F micromanometer-tipped catheter was inserted into the right carotid artery and advanced into the LV to determine LV pressure. With the rat anesthetized lightly and breathing spontaneously, LV pressure was recorded on a multichannel electrophysiology instrument . Heart rate (HR), left ventricular systolic pressure (LVSP), LV end-diastolic pressure(LVEDP), maximum and minimum values of rate of change in LV pressure . The left ventricular mass index was calculated and the left ventricular infarct area ratio was determined.Results were expressed as mean ± SD. Group comparisons were made with analysis of variance (ANOVA), followed by the LSD test to identify differences among various groups. A value of P<0.05 was considered statistically significant.There was no significant difference in weight, left ventricular mass index, and infarct area ratio for each group four weeks post-MI. See .Four weeks post-MI, EF and FS of MI group were significantly reduced . EDV and ESV were significantly increased. EF and FS in RD3+MI group, MI1+RD group and MI7+RD group, compared with MI group, were significantly increased, but were lower than normal (P<0.05). EDV and ESV of these three groups were found to be significantly lower than the MI group (P<0.05). See .Max (P<0.05) and dP/dtMin (P<0.05). Improvements in RD3+MI and MI1+RD groups were better than the MI7+RD group, but did not reach statistical significance (P>0.05). , decreased LVEDP (P<0.05), and increased dP/dt05). See .Four weeks post-MI, compared with the normal control group, urine output in the MI group was significantly reduced from 23.83±1.9 ml to 14.13±3.8 ml and urinary sodium excretion was decreased from 0.259±0.061 mmol to 0.138±0.019 mmol (P<0.05). As shown in When comparing MI group rats four weeks post-MI with N group, there is a significant increase, but there was no significant difference between the RD group and N group.The RD3+MI, MI2+RD, and MI7+RD groups had significantly decreases when compared with the MI group respectively, but were all higher than the N group (P<0.05), with no significantly differences amongst the groups See .Max, and dP/dtMin, while LVEDV, LVESV, and LVEDP decreased significantly compared with the MI group, as shown in The present study demonstrated that RD, whether performed before or after MI, can both prevent and lessen the deterioration of LV function and LV dilatation post-MI, including significantly increased EF, LVSP, dP/dtRD before MI may reduce excessive sympathetic response in the acute phase of MI. Clinical studies have demonstrated that β-adrenergic receptor blockade is beneficial in heart failure due to the decreased cardiac sympathetic stress that could reduce myocardial oxygen consumption, myocardial damage, and myocardial cell apoptosis. The process of ventricular enlargement can be influenced by infarct size, ventricular wall stress, and neurohumoral factors, including adrenergic drive and the renin-angiotensin system. There was a significant decrease in BNP levels in MI rats with RD compared with MI group four weeks post-MI, with no significant differences among the RD groups. This result again confirms that RD actually reduced the LV filling pressure and lessened post-MI cardiac remodeling..MI rats had severe water and sodium retention at four weeks post-MI. Urine volume and urinary sodium excretion significantly reduced. The results are consistent with previous animal studies and the established pathogenic mechanism of chronic heart failure. Finaly, when compared with the normal group, rats of the RD group had slight increases in HR, and slight decreases in heart function and 24-hour urine sodium. We are considering that this may be due to the side effects of the RD procedure itself (such as the trauma caused by the procedure) and variation among the animal subjects, causing a greater standard deviation. Because there was no significant statistical difference, we believe that RD does not have a significant effect on normal rats.We know that myocardial infarction expansion, left ventricular dilation, and compensatory myocardial hypertrophy in non-infarcted regions are involved in ventricular remodeling after coronary occlusion. In our study, the MI group underwent significant cardiac function and hemodynamic changes compared with normal group. However, changes were not statistically significant when compared with the indicator of LVMI. Our findings were similar to those of Byung-Hee It is our deduction that this phenomenon may be due to a few factors. Primarily, different infarct sizes and different timing of measurements may explain some variation in results, since heart weight, especially the LV weight, depends on the balance between tissue loss in the infarcted region and compensatory hypertrophy of surviving myocardium. This indicates that if the changes in LVMI during remodeling are to be observed, other non-infarction heart failure models may be necessary.In addition, there were also limitations to standardization by weight, since weight might be affected by water and sodium retention. When collecting samples, there were variations in the amount of interventricular septal tissue collected, and there were also variations in degree of drying after washing with normal saline. Another factor may have been insufficient observation time.Due to lack of detection techniques and experimental scales, we did not measure indices such as blood or tissue norepinephrine or β receptors, which reflected the activity of the sympathetic nervous system and the reconstruction of the sympathetic nervous system. Blood content changes of RAAS components were not measured either. Besides BNP, indices such as endothelin were not able to be measured. These indices are very important to RD research in post-MI heart failure.Therefore, after it was confirmed that RD improves left ventricular remodelingcardiac function, water and sodium excretion in rats with post-MI heart failure, an in-depth study should be conducted in further studies.Our study demonstrates that RD has a clear preventive and therapeutic effect on post-MI cardiac remodeling through lessening left ventricular remodeling, increasing cardiac function and water excretion, decreasing BNP levels, with the effect lasting at least four weeks. There were no significant differences for denervation procedures that took place at different times in the course of illness. Cardiac function, hemodynamics, BNP levels, urine volume and urine sodium discharge in normal rats were not affected by RD.The primary mechanisms of heart failure after AMI include ventricular remodeling and cardiac sympathetic remodeling, chronic over-activation of the sympathetic nervous system, renal sympathetic nerve activation and secondary RAAS activation. However, previous basic and clinical studies indicate that even though surgical renal denervation causes great trauma, and that there are many complications or adverse effects related to the procedure itself or neurovascular damage, the effects of RD are complete and precise.


Heart failure remains a major cause of mortality in the United States, despite advancing technologies, newer methods of treatment, and novel devices. To evaluate such novel devices, a large-animal model of chronic heart failure is critical in carrying out preclinical animal studies.We evaluated the efficacy of oral monensin in inducing stable heart failure in five Jersey calves. Various doses of monensin were administered. Hemodynamics, pressure–volume loops, echocardiographic measurements, extent of tissue perfusion, and histopathologic data were recorded before and after induction of heart failure.Responses were variable in the animals. One experiment showed a significant decrease in cardiac output within one week, associated with simultaneous increases in left atrial pressure, central venous pressure, and mean pulmonary artery pressure. Left ventricular pressure-volume loops showed that the slope of the end-systolic pressure-volume relation decreased markedly between the baseline and terminal study, suggesting a decrease in contractility. Echocardiographic studies indicated a decrease in ejection fraction. Histopathologic analysis in cardiac tissue showed extensive fibrosis and necrosis.We demonstrated the feasibility of inducing and maintaining severe yet stable heart failure for up to 3 weeks in a calf model by administration of oral monensin. Despite optimal medical therapy, nearly 300,000 patients die from heart failure each year in the United States . About 1It is important to evaluate the efficacy of these new technologies in preclinical animal studies. Large-animal models, such as calves, are frequently used because they bear some similarities to human cardiac anatomy and physiology; such models are useful in overcoming device fitting problems, as well. A healthy calf model is appropriate for demonstrating device biocompatibility; however, stable large-animal models of chronic stable heart failure are needed to evaluate the efficacy of innovative therapeutic strategies against heart failure. One study evaluating monensin toxicosis in calves suggested that this species may provide a valuable model of inducible chronic heart failure as this model is effective without using invasive procedures . HoweverThis study was approved by the Cleveland Clinic’s Institutional Animal Care and Use Committee. All animals received humane care in compliance with the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press (revised 1996).Streptomyces cinnamonensis. It is approved by the US Food and Drug Administration to treat ruminant coccidiosis and to improve milk production efficiency in dairy cows. However, in high doses, monensin causes cardiac toxicity, documented in the literature by accidental or intentional administration of higher than recommended doses of monensin to many species, including sheep  were used in this pilot study. Each animal was fasted for 12 h before surgery. Anesthesia was induced with an intramuscular injection of ketamine, with isoflurane given via mask inhalation. After endotracheal intubation, anesthesia was maintained with isoflurane (0.5–2.5%). A fluid-filled pressure monitoring line was inserted into the jugular vein to monitor central venous pressure (CVP). A median sternotomy approach was used for the first three experiments for the purpose of performing pressure-volume loop study, while a left thoracotomy was used for the next two experiments. A fluid-filled line was inserted into the pulmonary artery to monitor pulmonary artery pressure (PAP). A 28-mm Transonic flow probe  was placed around the ascending aorta to monitor cardiac output (CO). A fluid-filled line was placed within the left atrium for left atrial pressure (LAP) monitoring. An arterial fluid-filled line was connected to a side port of a carotid sheath to monitor arterial pressure (AoP). A conductance catheter with two Millar pressure sensors  was inserted through the carotid sheath into the left ventricle (LV) to monitor LV pressure-volume (PV) loops in the first three experiments. Umbilical tapes were placed around the superior vena cava and inferior vena cava. A two-dimensional epicardial echocardiogram (2D EE) was performed to confirm the position of the conductance catheter, for calibration of the conductance catheter measurements, and to assess left and right ventricular functions at baseline. The superior and inferior vena cavae were transiently occluded using the umbilical tapes to obtain the LV PV loops under various preloads.Postoperatively, the animals were allowed to recover in the chronic care unit (CCU), and standard postoperative care was given. Butorphanol (10–20 mg intravenously (I.V.) × every 12 h for 5 d, then PRN [“as needed”]) and flunixamine  were administered for breakthrough pain. Gentamicin (160 mg I.V. × every 8 h) and cefazolin (2 g I.V. × every 6 h) were given postoperatively for 7 d.After a 7-d recovery period, each calf was sedated with intravenous xylazine (6–8 mg). An oral-gastric tube was inserted, followed by a Corpak feeding tube, which was inserted through the gastric tube. A single dose of monensin  suspended in 60 mL of normal saline solution was injected down the Corpak tube using a 60-mL syringe. After the initial dose, the syringe was flushed multiple times with normal saline.Monensin blood plasma concentrations were measured 1 d after each dose was given. Levels of plasma renin activity, and the cardiac enzymes troponin T and creatine kinase-myocardial band (creatine kinase-MB) were measured before and then one week after each monensin administration. Successful induction of heart failure was defined as either a 20%–30% increase of left ventricular end-diastolic volume (EDV) above baseline, a 10–20 mm Hg decrease in mean systemic blood pressure below baseline, a 10 mm Hg increase in LAP and/or CVP above baseline, or a 20% decrease in CO below baseline.After 5 wk of heart failure induction, a second surgical procedure was performed in the surviving calves to obtain terminal hemodynamic data. Epicardial echocardiogram and LV PV loops studies were performed and compared with baseline measurements.Hemodynamic parameters were recorded hourly after the initial surgery by the animal monitor in the CCU and weekly via a data acquisition system . Data were stored on a hard disk for subsequent analysis by a laboratory computer. The following parameters were recorded: PAP , AoP , CVP and LAP through the fluid-filled catheters, heart rate via electrocardiogram, and CO by means of flow probe readings.As we previously reported , conductA Vivid 7 echocardiography machine  coupled to a 4S transducer (multifrequency transducer) was used in this study. For both initial and terminal studies, 2D EEs were performed during the surgical procedures. Two-dimensional transthoracic echocardiograms were performed at a single time point before drug administration, and weekly thereafter. The 2D EEs were used to calculate LV volumes and ejection fraction (EF) using Simpson’s biplane method.Regional blood flow was measured by using labeled microspheres . BioPAL microsphere injection was performed once in the CCU before monensin administration to get a baseline value, then weekly after monensin administration. Microspheres were injected into the left atrium through the LAP monitoring line, while a reference blood sample was withdrawn through a syringe pump from the carotid artery. Tissue samples harvested at autopsy and blood samples of interest were sent to the BioPAL laboratory for processing and evaluation of the regional blood flow.At the end of each study, the animal was killed by rapid intravenous injection of pentobarbital (50 mg/kg) and potassium chloride (240 mEq). Following sacrifice, a thorough autopsy was performed, and histological specimens were harvested from the heart for routine hematoxylin-and-eosin staining study under light microscopy (magnification of 100× with a 10× ocular lens). Moreover, samples from the LV free wall, septum, RV free wall, and kidney were obtained for the analysis of regional blood flow with microspheres.Table Experiment 1: The initial monensin dose given was 25 mg/kg, based on results from a study at the University of Louisville  one week after each dose administration. As shown in Table  and 3 onIn a previous study, elevation in cardiac troponin I was reported after administration of sodium monensin in horses . In our In this study, we demonstrated the feasibility of inducing and maintaining stable yet severe heart failure for up to 3 weeks in a calf by oral administration of monensin. The recorded changes in hemodynamic parameters in experiment 3 after dose 2, demonstrated by a marked decrease in CO and mean AoP accompanied by a similar increase in PAP, LAP and CVP, are consistent with heart failure and were stable for 3 weeks until the animal was electively sacrificed. The decrease in the slope of the ESPVR suggested a marked decrease in LV contractility. Measurements from experiment 3’s LV PV loops, hemodynamics, echocardiography, colored microspheres tissue perfusion study, and pathologic examination all confirmed severe, persistent cardiomyopathy. The model was associated with structural changes consistent with LV remodeling , reductiOur results demonstrated large variability in response to oral monensin among the five calves, ranging from the absence of heart failure with 60 mg/kg monensin in the first experiment to severe heart failure with 40 mg/kg monensin in experiment 5. As shown in Table There are several available large-animal models of heart failure, including models of tachycardia-induced heart failure , myocarThe model of chronic heart failure induced by monensin is more reliable than other models of drug-induced heart failure, since it overcomes the disadvantages of reversibility and the need for continuous drug infusion that characterizes most of these models, as in using drugs with negative inotropic effects . On the The ideal animal model of congestive heart failure should be able to mimic the progression of naturally occurring human congestive heart failure syndrome, characterized by a complex alteration in hemodynamics and geometry of the heart, as well as reflexes in the sympathetic nervous system, the cardiac endocrine system, and the renin-angiotensin system.The main limitation in this study was the small number of animals used. Although oral monensin was successful in inducing chronic stable heart failure in one animal, there was no uniform protocol to induce a reliable reproducible model among all the animals in this study.Although no conclusion can be presented, we have successfully administered monensin orally in our study to induce severe chronic stable heart failure; the main problem was to control the monensin blood concentration administering monensin this way probably due to a large variability of monensin absorption from the alimentary tract in cattle. Future investigations are required to further characterize the heart failure induced by monensin and the resulting impact on cardiac tissue and cardiac enzymes.


We sought to investigate the relationship between infarct and dyssynchrony post- myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality.Cine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 ± 2 days (early post-MI), and 33 ± 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro-anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice.Mean infarct size was 21 ± 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 ± 1.6% vs. -18 ± 2.5% (early) and -17 ± 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early  and late post-MI . The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 ± 7 ms to 50 ± 10 ms  to 54 ± 19 ms , with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 ± 2.4 cm/s), when compared to peri-infarct (18.7 ± 10.3 cm/s) and remote myocardium (39 ± 20.5 cm/s).Mechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct. Cardiac resynchronization therapy (CRT) relieves symptoms, induces reverse remodeling, reduces heart failure hospitalizations, and improves survival in symptomatic heart failure patients with left ventricular systolic dysfunction and conduction abnormality -4. HowevThese clinical observations intensify the need for a more detailed investigation of regional mechanics following MI. Such knowledge may potentially help explain the differences in response to CRT between ischemic and non-ischemic CM and could potentially assist in developing novel treatment strategies for dyssynchrony in the post-MI setting. To date, most physiologic, mechanical, cellular, and molecular data concerning CRT have been generated in a well-validated tachy-pacing model of heart failure -14, but Cardiovascular magnetic resonance (CMR) is an attractive modality to study dyssynchrony because it permits simultaneous assessment of anatomy, scar burden, and myocardial deformation at high spatial and temporal resolution in experimental  models and patients. In this study, we used a well-characterized porcine model of MI  to deterOur experimental protocol was approved by the Institutional Animal Care and Use Committee.Ten young farm pigs weighing 25 to 35 kg were subjected to percutaneous occlusion of the left anterior descending artery as was previously described . AnimalsStudies were performed using a clinical Philips 3.0T Achieva MR scanner  equipped with a six-channel cardiac phased array surface coil. Animals were mechanically ventilated, anaesthetized, and paralyzed for the duration of imaging. Cine, contrast-enhanced and tagged images  were obt® ver. 7.6 . Please see additional file LV mass and volumes, late gadolinium enhancement (LGE), and circumferential strain (eC) were measured using a custom-built software tool developed using MatlabDyssynchrony index was calculated as the standard deviation of time to peak eC (TTP) for 16 segments per animal, where time to peak strain was measured from the QRS complex. This index has been previously used to assess dyssynchrony in experimental and clinical studies ,13,17-20EAM was performed using the CARTO system  in all 6 pigs within 24 hrs of CMR and prior to sacrifice. Please see additional file All data were analyzed using JMP version 9 software . Continuous variables are expressed as mean ± SD. Differences between regions and time points were tested using two way repeated measures ANOVA and a paired t test. A p value < 0.05 was considered significant. Inter-observer reproducibility was tested in 63 randomly selected segments, at the early and late post-MI time-points.Of 10 animals, 4 died due to incessant ventricular fibrillation  leaving 6 animals for the study. We analyzed a total of 96 segments at baseline and 95 normal, 57 peri-MI and 33 MI segments at the early and late post-MI time-points. There was no significant difference in heart rate between the baseline, early and late post-MI time-points  and 172 (60%) of 288 total segments, respectively, at all 3 time-points. Since the yield was low and signal quality was unreliable for eR, we restricted all analysis to segmental eC only.Cine and LGE images were used to characterize the infarct. Infarction was located in the apical to mid-anterior wall and anterior septum. All MI segments had LGE of ≥ 90% of myocardial wall thickness and were transmural. Mean infarct volume was 21 ± 4% and 20 ± 6% of the LV myocardial volume at early and late time-points, respectively  wall thickness was lower in the MI segments compared to the normal segments at the early time-point, and further decreased at the late post-MI time-point  but decreased significantly between pre-MI and late post-MI . There was a non-significant trend towards decrease in peak eC between early and late post MI . However, despite these statistical differences, eC values at all 3 time-points were within normal range . Peak eC in peri-MI  and MI segments . There was no significant decrease in peak eC in peri-MI and MI segments between early and late post MI . Peak segmental eC decreased significantly in normal, peri-MI, and MI segments between early  and late MI time points . The mean TTP for all 16 segments was 300 ± 28 ms at baseline. There were no statistically significant differences in TTP between normal and peri-MI segments at the early  and late post-MI  time-points. In contrast, TTP was significantly longer in MI segments compared to normal and peri-MI segments at the early  and late post-MI time-points . TTP in peri-MI segments did not change significantly from pre-MI to early to late post MI . TTP in MI segments increased significantly from pre-MI to early and late post MI . There was no significant increase in TTP between early and late post MI  472 ms (early), 460 ms (30 days) and 483 ms (135 days); Animal # 2) 492 ms (early), 512 ms (30 days) and 450 ms (135 days). These 2 case examples appear to support our earlier observations concerning the lack of significant additional dyssynchrony between 1 and 4 weeks of post-MI.2 = 0.01, p = 0.14), peri-MI  and MI segments .We found no relationship between regional strain and dyssynchrony when considering normal segments .In a closed-chest porcine model, mechanical dyssynchrony, as evidenced by the standard deviation in TTP, occurs early after MI and does not significantly worsen in the near term. Dyssynchrony originates primarily from delayed electrical and mechanical activation of the infarcted region.Myocardial infarction and its common consequence, heart failure, present a significant health problem in the United States and the world . DespiteOur model allows us to reliably characterize the distribution and extent of infarct by LGE. Similarly, we were able to evaluate the time course of changes in regional contractility and dyssynchrony following MI using CMR tagging. Unlike echocardiography, tagged CMR allows evaluation of myocardial strain at high spatial resolution and reproducibility. Strain, which evaluates regional myocardial deformation, is more reflective of myocardial mechanics than displacement mapping using parameters such as tissue velocity which are prone to artifacts from translational motion and tethering . These aOur study demonstrates significant mechanical dyssynchrony within days of an MI, which is in concordance with previously published work using echocardiography in clinical populations . EchocarAnother important finding of our study is that delayed mechanical activation is not linked to reduced regional function per se. Regional contractility and conduction velocity were lowest in MI segments and intermediate in peri-MI segments, unlike the study by Klemm et al.  in patie2+handling and Ca2+ transients that have been previously reported in infarct border-zone myocytes [Conduction velocity was significantly lower in the infarct and infarct border-zone (IBZ) when compared to the remote myocardium. The infarct was the latest activated region because of very slow conduction, indicating that reduction in wave propagation velocity is the most important contributor to the time delay in regional contraction that we observed. Impulse propagation in the heart is dependent on active membrane properties determined by the ion channel composition, cell size, gap junction function and distribution . Previoumyocytes , in combAnother possible explanation for lack of a relationship between delayed mechanical activation and reduced regional function is infarct expansion, although we did not see an increase in the number of delayed-enhancement segments late post-MI, suggesting this was not a dominant mechanism in our study. Lastly, differences may be due to segment definition, compared to previous studies: a peri-MI segment in our study was a segment adjacent to an MI segment Figure  and was 1) delayed electrical and mechanical activation of the infarct is the main cause of dyssynchrony; 2) despite adverse remodeling of the left ventricle post-MI, further worsening of mechanical dyssynchrony does not occur. Hence, assessment of dyssynchrony one week post-MI or before discharge from the hospital, should be adequate to assess the consequences of MI on mechanical synchrony. The one week time point was chosen for logistical reasons in this animal study. However, based on the evolution of myocardial infarction, imaging any time in the first week post-MI should suffice. While the relationship between scar burden and lack of response to CRT in patients with ischemic CM has been reported before [There are several clinical implications of our findings for CRT in patients with ischemic CM. Our data indicate that d before ,36, the d before  was causd before .The sample size is relatively small. However, power calculations and our results suggest that it is adequate for this analysis. Larger MIs resulted in significant animal mortality so we limited the size of the MI to approximately 20%. Hence, we are unable to assess the relationship between infarct size and dyssynchrony. Additionally, we did not study changes in regional mechanics beyond 4 weeks; a longer term study is logistically challenging and prohibitively expensive. Since this is not an intervention study we cannot assess the response of ischemic CM to CRT or medications like beta blockers. Furthermore, due to poor radial strain quality we were unable to examine the relative value of eR and eC. However, the low feasibility of eR suggests it may not be as useful in this model. Lastly, due to logistic difficulties we were unable to perform concomitant echocardiography evaluation of dyssynchrony in this study that would have allowed better comparisons to published echo-based data. Conduction velocity measurements using EAM are sensitive to mapping density as well as underlying myocardial architecture (uniform anisotropy), with longitudinal CV being significantly greater than transverse CV in normal myocardium. This could have resulted in the large variation in CV observed in normal myocardium. Lastly, we did not isolate myocytes for cellular studies which could have provided insights into the electrical and mechanical changes that we observed.Mechanical dyssynchrony occurs early after acute MI with non-significant changes in the near term. Delayed mechanical activation is noted primarily in the MI segments. Further imaging and cellular studies are needed to investigate dyssynchrony and the effects of interventions such as beta blockers, stem cell therapy and CRT in ischemic cardiomyopathy.CRT: cardiac resynchronization therapy; LV: left ventricle; CM: cardiomyopathy; MI: myocardial infarction; CMR: cardiovascular magnetic resonance, zHARP: z-encoding harmonic phase imaging; EAM: Electroanatomical Mapping; eC: Circumferential Strain; eR: Radial strain; TTP: Time to peak strain; EF: Ejection Fraction; IBZ: Infarct border-zone; CV: Conduction velocity.Dr. Calkins receives research support from Medtronic, St Jude Medical, and Boston Scientific and serves as a consultant for Medtronic. All other authors have reported that they have no relationships to disclose.KZA: made substantial contributions to acquisition and analysis of data and has been involved in drafting and revising the manuscript. MST: made substantial contributions to analysis and interpretation of data and has been involved in drafting and revising the manuscript. TS: made substantial contributions to conception and design and acquisition of data and has been involved in revising the manuscript. SS: made substantial contributions to analysis and interpretation of data and has been involved in revising the manuscript. EVP: made substantial contributions to acquisition and analysis of data. AY: made substantial contributions to acquisition of data. HA: made substantial contributions to data analysis and has been involved in drafting the manuscript. VLD: made substantial contributions to analysis and interpretation of data and has been involved in revising the manuscript. HC: made substantial contributions to data acquisition and interpretation. JLP: made substantial contributions to conception, design and interpretation of data and has been involved in revising the manuscript. TPA: made substantial contributions to conception, design and analysis and interpretation of data and has been involved in drafting and revising the manuscript. MRA: made substantial contributions to conception, design, acquisition and interpretation of data and has been involved in drafting and revising the manuscript. All authors read and approved the final manuscript.Supplemental Material and Methods. The file contains detailed descriptions of the cine, tagging, and delayed enhancement imaging protocols and image analyses performed in this study.Click here for fileGraphical description of infarct, peri-infarct and normal segments. The figure shows 1) infarct segments which were defined as those with > 25% delayed enhancement and < 10% strain, 2) peri-MI segments were defined as those immediately adjacent to an MI segment in the 3-dimensional space, and 3) the remaining segments which were considered as normal segments.Click here for file


Atrial fibrillation (AF) is associated with different amounts of diffuse fibrosis, which has impact in the therapy response. CMR is able to assess myocardial fibrosis using late gadolinium enhancement (LGE) and chamber function.The aim of this study was to assess, in patients with AF if the presence and extension of atrial fibrosis was related with atrial size and function.47  consecutive patients (pts) with paroxysmal AF and indication to ablation were included. Exclusion criteria for CMR: non-sinus rhythm and general contra-indications. Before ablation all underwent CMR for left atrial angiography for CARTO mapping. Using CMR, the following variables were assessed: left ventricle (LV) and left atrium (LA) volumes and ejection fraction , LV LGE was assessed as presence and amount (LGE mass/LV mass). LA LGE location was assigned to 3 atrial walls: anterior, posterior and septal. The extension was classified in 3 degrees, according to the number of atrial walls with LGE: 1=one wall, 2=two walls; 3=three walls. For CMR analysis dedicated software was used (Philips View Forum Release 6.1).All studies yielded good image quality. LV end-diastolic volume was 68±5ml/m2 and normal in all; LV ejection fraction was 58±4%(48-67), normal in all (in 2 borderline); 11 pts showed minimal LV LGE involving one or two segments with 0.02% of fibrosis mass/LV mass; mean LA volume was 115±21ml (increased in 45% o patients); mean LA ejection fraction was 45±11% (reduced in 65%). Type 1 LGE was found in 17 pts, type 2 in 22 and type 3 in 8 pts. Comparing the groups with the 3 LGE types, pts with type 3 LGE had larger LA volumes and lower ejection fraction in comparison with type 1 LGE pts (p=0.004 and p=0.001 respectively). No difference was found between other groups. No relationship was found with LV volumes, ejection fraction and amount of fibrosis.In pts with paroxysmal AF pre-ablation, atrial fibrosis as assessed semi-quantitatively by CMR was associated to larger left atrial volume and lower ejection fraction, which are determinant substrates for the outcome.


Feature Tracking software offers measurements of myocardial strain, velocities and displacement from cine cardiovascular magnetic resonance (CMR) images. We used it to record deformation parameters in healthy adults and compared values to those obtained by tagging.We used TomTec 2D Cardiac Performance Analysis software to derive global, regional and segmental myocardial deformation parameters in 145 healthy volunteers who had steady state free precession (SSFP) cine left ventricular short  and long axis views  obtained on a 1.5 T Siemens Sonata scanner. 20 subjects also had tagged acquisitions and we compared global and regional deformation values obtained from these with those from Feature Tracking.For globally averaged measurements of strain, only those measured circumferentially in short axis slices showed reasonably good levels of agreement between FT and tagging (limits of agreement −0.06 to 0.04). Longitudinal strain showed wide limits of agreement (−0.16 to 0.03) with evidence of overestimation of strain by FT relative to tagging as the mean of both measures increased. Radial strain was systematically overestimated by FT relative to tagging with very wide limits of agreement extending to as much as 100% of the mean value (−0.01 to 0.23). Reproducibility showed similar relative trends with acceptable global inter-observer variability for circumferential measures (coefficient of variation 4.9%) but poor reproducibility in the radial direction (coefficient of variation 32.3%). Ranges for deformation parameters varied between basal, mid and apical LV levels with higher levels at base compared to apex, and between genders by both FT and tagging.FT measurements of circumferential but not longitudinally or radially directed global strain showed reasonable agreement with tagging and acceptable inter-observer reproducibility. We record provisional ranges of FT deformation parameters at global, regional and segmental levels. They show evidence of variation with gender and myocardial region in the volunteers studied, but have yet to be compared with tagging measurements at the segmental level. Left ventricular myocardial systolic strain and deformation parameters alter early in disease pathogenesis ,2 and vaFeature Tracking has been used to quantify myocardial strain at a global level and within individual short axis slices in several studies -8. HowevThe CMR images from one hundred and forty five healthy volunteers, recruited by advertisement as controls for research studies over a two year period, were analysed. None of the subjects had documented cardiovascular risk factors, cardiac disease or other medical problems relevant to cardiac function. All subjects had undergone the same non-contrast, left ventricular, SSFP CMR acquisition protocol on a Siemens 1.5 T Sonata scanner. Anthropometric measurements (height and weight), blood pressure and fasting blood tests (lipid profiles and glucose) had been obtained at the time of the CMR scan. The research studies were approved by the local ethics committee and informed consent for participation obtained from all subjects.All images were recorded at 1.5 T with a 16 channel receiver coil without the use of contrast following the same standardisation protocol for all acquisitions. Image acquisition was prospectively electrocardiogram (ECG) gated with a precordial three lead ECG and acquired during end-expiratory breath holding. SSFP cine sequences were used to acquire localisation images followed by a SSFP ventricular short axis stack to obtain coverage of the entire left ventricle (LV) and horizontal long axis (HLA), vertical long axis (VLA) and left ventricular outflow tract views (LVOT) cine in 1 cm slices. Image acquisition parameters were echo time (TE) of 1.5 ms, a repetition time (TR) of 3.0 ms, temporal resolution 39.0 ± 2.8 ms and a flip angle of 60º, field of view 360 mm, slice thickness 8 mm, acquisition window 800 msec. In 20 subjects, a gradient echo-based tagging pulse sequence had also been performed in the long axis  and in the basal, mid ventricular and apical short axis slices with a segmented K-space, multi-shot sequence . Slice positions were chosen from the images obtained for the left ventricular short axis SSFP stack. The nearest slice to the base in which a complete circle of myocardium was visible throughout the cardiac cycle was selected as the basal slice. The mid-ventricular and apical slices were then selected with sequential 2 cm gaps towards to the apex [2D Cardiac Performance Analysis Software  was used to obtain strain quantification directly from cine images. The same experienced operator performed all measures following a standard protocol taught by the software manufacturer. In 12 subjects measures were repeated after an interval of 3 weeks by both this observer and a second experienced observer to assess inter and intra-observer agreement for measures. Following uploading of the image, the brightness is optimised to ensure optimal endocardial / blood pool discrimination. Points are placed along the endocardial border  and both the epicardial and endocardial borders . The software then takes an endocardial border line through the marked points and searches for the most closely matching features along its length in subsequent frames. In a proportion of subjects it was visually apparent the software failed to track myocardial motion in certain segments. Poor tracking was considered to be present when the movement of the points along a portion of the border deviated from the movement of the apparent endocardial border by more than 50% of the myocardial width. A record was kept of which segments failed to track and these segments excluded from subsequent analysis. Longitudinal strain, strain rates, velocities and displacement were obtained from the long axis views. Circumferential and radial strain, strain rates, velocities as well as basal and apical rotation and rotation rates were measured from the short axis SSFP views. Short axis slice position was selected in the same way as for tagging image acquisition and, therefore, corresponding slices were used in those who had both sets of measures. Values were recorded at a segmental, regional level  and global level.In those subjects who had also undergone tagging studies semi-automated analysis of the tagged cine images was performed using CIM software . A grid was aligned automatically to the myocardial tagging planes at end diastole. End systole is determined visually, and tags are adjusted at each frame through the cardiac cycle. Circumferential, longitudinal and radial myocardial strains and strain rates were calculated by the software from the motion of the intersected tag lines. Global values were recorded. Regional values were calculated at basal, mid and apical levels.Summary variables for subject characteristics and normal ranges of deformation parameters are presented as mean ± standard deviation (SD). Inter and intra observer variability was assessed using the coefficient of variation (CV). Comparison of demographic, clinical and myocardial deformation data between genders was performed by paired Student t test for normally distributed variables and Wilcoxonian test for non-normally distributed variables. Distribution of the variables was assessed using the Kolomogrov Smirnov test. Comparisons of myocardial deformation parameters between myocardial regions was performed by ANOVA with a repeated measure design using a Greenhouse-Geisser correction followed by paired Student t-test to define the differences. Comparison of feature tracking derived values with tagging results was assessed using Bland Altman  analysisBaseline characteristics of the 145 subjects in the study cohort are recorded in Table -1 vs. 1.13 ± 0.49 s-1, p = 0.03), velocities  and displacement .Ranges for deformation parameters derived by Feature Tracking at a global and regional level are shown in Table Analysis of a complete data set using Feature Tracking was quicker than by tagging . The plots of Figure -1, -0.53 to 0.11) and the poorest agreement with radial strain rate . Larger biases and limits of agreement were seen when comparing feature tracking with tagging at a regional level compared with a global level although again, the agreement for radial strain was poorest.Absolute values for tagging derived strain for each gender are presented in Table This study documents ranges for all left ventricular myocardial systolic strain parameters as well as myocardial displacement and velocities recorded using Feature Tracking down to a segmental level in a large group of healthy subjects, although the latter have yet to be compared with an alternative type of measurement. The results showed regional variation, with higher strain at the base than apex, as well as gender differences.Feature Tracking software delivers outputs of myocardial strain, segmental velocity and displacement parameters which are relatively quick in terms of image acquisition and post processing. The technique avoids the additional time needed for either tissue phase mapping or tagging and raises the possibility of retrospective analysis of existing CMR datasets. We found the software could be easily applied to existing SSFP cine sequences and was apparently able to track 90% of imaged segments. This compares favourably to echocardiographic studies of regional speckle tracking analysis in which strain typically can only be measured in around 80% of segments -13; presNevertheless, as others have reported ,14,15, wTagging measures myocardial strain from the changing in-plane separations of tags that mark the intersections of orthogonally orientated tagging planes. They are therefore relatively unaffected by a through-plane component of motion. In contrast, feature tracking analyses motion in a 2D plane of features along a myocardial band defined by the endocardial border. The algorithms used by TomTec to track features are based on an adaptation of particle velocimetry algorithms in common use in multiple technologies including speckle tracking. They use voxel patterns within the image identified during initial contour application and subsequent searching between frames based on a hierarchical protocol that allows for reducing region of interest to improve accuracy, recognition of variation in motion between base and apex and rules regarding endocardial and epicardial boundaries . InteresChanges in the voxel pattern during the cardiac cycle within the myocardium may have an impact on consistency of feature tracking and account for some variation in strain measures, particularly in the radial direction. For instance, it is possible the compaction and exclusion of blood from interstices in trabeculated myocardium at end systole may alter voxel appearances in this region sufficiently to make accurate tracking difficult. The higher degree of trabeculations seen at the LV apical level when compared with the basal level may account, in part, for the increased variability in measurements seen in this region.These differences in the approach of feature tracking prompted our study to define feature tracking-specific ranges for strain -8,18. NoOur results showed some consistent trends between techniques in our study population. For instance, deformation values varied between genders and myocardial regions when assessed by both feature tracking and tagging ,23. MultFT measurements of circumferential but not longitudinally or radially directed global strain showed reasonable agreement with tagging and acceptable inter-observer reproducibility. We recorded provisional ranges of FT deformation parameters at global, regional and segmental levels in healthy volunteers. The software rapidly extracts these measures from existing SSFP cine images. Our results show evidence of variation with gender and myocardial region in the volunteers studied, but have yet to be compared with tagging measurements at the segmental level.CMR: Cardiac magnetic resonance; ECG: Electrocardiogram; HARP: Harmonic phase; HLA: Horizontal long axis; LOA: Limits of agreement; LV: Left ventricle; LVOT: Left ventricular outflow tract; SD: Standard deviation; SSFP: Steady state free precession; TE: Echo time; TR: Repetition time; VLA: Vertical long axis.The authors declare that they have no competing interests.DA was involved in the conception and design of the study; acquisition of data, analysis, drafting and approved the manuscript. AL carried out acquisition of data, analysis, revising the draft critically for important intellectual content and has given final approval of the version to be published. ML was involved in acquisition of data, analysis and has given final approval of the version to be published. AR was involved in analysis and has given final approval of the version to be published. JF carried out acquisition of data, revising the draft critically for important intellectual content and has given final approval of the version to be published. SM was involved in revising the draft critically for important intellectual content and has given final approval of the version to be published. AN was involved in revising the draft critically for important intellectual content and has given final approval of the version to be published.SN was involved in revising the draft critically for important intellectual content and has given final approval of the version to be published. HB was involved in revising the draft critically for important intellectual content and has given final approval of the version to be published. SEP was involved in revising the draft critically for important intellectual content and has given final approval of the version to be published. PL was involved in the conception and design of the study; revising the draft critically for important intellectual content and has given final approval of the version to be published. All authors read and approved the final manuscript.This work was funded by a grant from the Engineering and Physical Sciences Research Council (EP/G030693/1) and supported by the Oxford British Heart Foundation Centre of Research Excellence and the National Institute for Health Research Oxford Biomedical Research Centre. Dr P Leeson is supported by the British Heart Foundation. Dr S Petersen was directly funded by the National Institute for Health Research Barts and The London Biomedical Research Unit.


Existing methods require long breath holds that are demanding for many cardiac patients. In this work we propose and validate a novel, clinically applicable, pulse sequence for myocardial T1-mapping that is compatible with typical limits for end-expiration breath-holding in patients.T1 mapping allows direct In-vivo myocardial T1-mapping using this method and the previous gold-standard (MOLLI) was performed in 10 healthy volunteers at 1.5T and 3T, 4 volunteers with contrast injection at 1.5T, and 4 patients with recent myocardial infarction (MI) at 3T.The Shortened MOdified Look-Locker Inversion recovery (ShMOLLI) method uses sequential inversion recovery measurements within a single short breath-hold. Full recovery of the longitudinal magnetisation between sequential inversion pulses is not achieved, but conditional interpretation of samples for reconstruction of T1-maps is used to yield accurate measurements, and this algorithm is implemented directly on the scanner. We performed computer simulations for 100 ms<T1 < 2.7 s and heart rates 40-100 bpm followed by phantom validation at 1.5T and 3T. In-vivo, ShMOLLI measurements required 9.0 ± 1.1 s (MOLLI = 17.6 ± 2.9 s). Average healthy myocardial T1 s by ShMOLLI at 1.5T were 966 ± 48 ms (mean ± SD) and 1166 ± 60 ms at 3T. In MI patients, the T1 in unaffected myocardium (1216 ± 42 ms) was similar to controls at 3T. Ischemically injured myocardium showed increased T1 = 1432 ± 33 ms (p < 0.001). The difference between MI and remote myocardium was estimated 15% larger by ShMOLLI than MOLLI (p < 0.04) which suffers from heart rate dependencies for long T1. The in-vivo variability within ShMOLLI T1-maps was only 14% (1.5T) or 18% (3T) higher than the MOLLI maps, but the MOLLI acquisitions were twice longer than ShMOLLI acquisitions.We found good agreement between the average ShMOLLI and MOLLI estimates for T1 < 1200 ms. In contrast to the original method, ShMOLLI showed no dependence on heart rates for long T1 values, with estimates characterized by a constant 4% underestimation for T1 = 800-2700 ms. ShMOLLI is an efficient method that generates immediate, high-resolution myocardial T1-maps in a short breath-hold with high precision. This technique provides a valuable clinically applicable tool for myocardial tissue characterisation. In cardiovascular magnetic resonance (CMR), tissue contrast is generated by a combination of intrinsic tissue properties such as spin-lattice (T1) and spin-spin (T2) relaxation times, and extrinsic properties such as imaging sequence and settings. Signal intensity in conventional CMR images is displayed on an arbitrary scale, and thus is not suited to comparison between subjects. T1-mapping provides a quantitative surrogate marker for the cellular environment of the myocardial water allowing direct comparison between patients and examinations, which can operate without the need for exogenous contrast agents.T1 relaxation times depend on the composition of tissues, and each tissue type exhibits a characteristic range of normal values at a selected magnetic field strength ,3, heartAn established method for myocardial T1-mapping is the modified Look Locker inversion recovery (MOLLI) pulse sequence . It mergin-vivo for normal human myocardium at 1.5T and 3T. To extend the in-vivo validation range we also present findings in four human subjects with recent myocardial infarction and four normal subjects after gadolinium contrast.We hypothesise that it is possible to determine T1 maps of the heart with high precision in a short breath-hold. We thus present a shortened alternative to MOLLI (ShMOLLI) which can generate rapid and high-resolution myocardial T1-maps in a single short breath-hold of only 9 heartbeats. We investigate the accuracy of T1 measurements by ShMOLLI against MOLLI in simulation and gel phantom experiments over a wide range of heart rates and T1 values. The findings are validated RR , which does not approximate to full recovery of the magnetization  by implementing equations for the piece-wise calculation of longitudinal magnetisation (Mz(t)) and the signal samples generated by a train of arbitrarily-spaced ideal excitation pulses. Inversion pulses are assumed to be perfect 180° excitations; readouts are simulated as single pulses of 35°. Both sequences had three IR epochs. Simulations were performed for MOLLI based on its optimised variant , which cn Figure .Simulations using simplified pulse sequences outlined in Figure nd and 3rd IR of ShMOLLI do not fit the simple method of pooling data together into a single IR equation as outlined for MOLLI [RR < T1 < TRR) samples 1-6 are used. For very short T1 (< 0.4TRR), samples 1-7 are utilised. As the T1 is not known accurately the inclusion thresholds 0.4TRR and TRR are modified depending on the fit error.Significant shortening of the recovery epochs means that Mz can be severely affected by preceding IR epochs in the excitation sequence as demonstrated for long T1 values in Figure or MOLLI  and woulor MOLLI . For shoThe MOLLI and ShMOLLI acquisitions used a research sequence provided by Siemens  utilising the optimised parameter set for MOLLI  and ShMOFifteen 50 ml Agarose and NiCl gel phantoms  with T2~Reference T1 relaxation times were calculated offline based on images collected using slice-selective IR with non-segmented spin echo readout. TI = 33, 100, 300, 900, 2700, 5000 ms. TR/TE = 10 s/6.3 ms; 80 phase encoding steps with total image acquisition time of 13 minutes. Sizing and positioning were identical to the studied MOLLI methods. Regions of interest were placed in each tube using an automated method and reference T1 s were fitted per pixel and a mean T1 determined.Ethics approval was granted for all study procedures and informed consent was obtained from all subjects.10 normal volunteers  underwent CMR imaging at 1.5T and 3T on the same day. Following standard planning, end-expiration basal, mid-cavity and apical short-axis images using MOLLI and ShMOLLI were collected. Images for specific TI were collected using exactly the same SSFP readouts for both methods to allow direct comparisons, typically: TR/TE = 2.14/1.07 ms, flip angle = 35°, FOV = 340 × 255 mm, matrix = 192 × 144, 107 phase encoding steps, interpolated voxel size = 0.9 × 0.9 × 8 mm, GRAPPA = 2 with 24 reference lines, cardiac delay time TD = 500 ms; 206 ms acquisition time for single image. A single slice, which was judged to have the "best quality" at the time of scanning, was repeated twice at the end of the protocol to assess short-term intra-scan variability of the T1 measurements; this was not performed in the first pilot case. Offline post-processing involved manual tracing of endo- and epi-cardial contours for analysis of the T1 measurements in myocardial segments 1 to 16 of the American Heart Association (AHA) 17-segment model [rd order polynomial for the purpose of constructing Bland-Altman plots.Matching pairs of ShMOLLI and MOLLI pre-contrast and post-contrast T1 maps were obtained in 4 female subjects (61 ± 3 years old) without pre-existing cardiac disease who underwent a separate research protocol at 1.5T. Subjects underwent adenosine stress perfusion at 140 μg/kg/min for 3 min, followed by a bolus of Gd . After 20 minutes, resting perfusion imaging was performed using 0.03 mmol/kg of Gd followed immediately by a top-up Gd of 0.10 mmol/kg for LGE imaging. Matching T1-maps were obtained at baseline and ~14 minutes after adenosine stress perfusion. Finally, 4 pairs of images were collected before, and one after, the LGE images. The dynamic evolution of T1 recovery after the final Gd bolus was corrected with 34 patients  underwent CMR at 3T following the diagnosis of a first acute ST-elevation type myocardial infarction (STEMI) post primary percutaneous coronary intervention (PCI). LGE images were obtained 24-48 hours post acute infarct . T1-mapsUnless stated otherwise, the results are presented as mean ± SD/mixed SD, where the "mixed SD" is estimated as the independent combination of average individual SD and the interindividual SD. For estimation of the relative variability we use the coefficient of variation (CV = 100%*SD/Mean). The term "noise penalty" is used to describe the expected relative increase in CV resulting from predicable factors, i.e. the reduced number of samples. Significance of the differences between population means is calculated using 2-tailed Student T-tests, paired whenever possible, and quoted when p <0.05.The accuracy of both methods is dependent on the T1 and heart rate. Generally, as HR and T1 increase, the T1 measurements diverge increasingly from the ideal identity line Figure . This isThe variability of T1 measurements across all simulations or pixels is shown as whiskers in Figure In normal control volunteers, the myocardial ShMOLLI and MOLLI T1-maps did not show any visual differences Figure . The imaThe average T1 values for myocardial segments derived using both ShMOLLI and MOLLI at 1.5T and 3T are presented in Figure Analysis of differences between methods Figure  revealedin-vivo data in Figure in-vivo in the low T1 regime predicted in simulation and phantom measurements.None of the subjects demonstrated LGE lesions. The baseline T1 values were 982 ± 28 ms, comparable with other controls at 1.5T. Depending on the dose of gadolinium and time point the T1 showed expected shortening with the lowest average myocardial T1 of 135 ± 33 ms and subsequent recovery towards normal values Figure . The difAs in normal controls, the image acquisition in patients was much faster using ShMOLLI 9.9 ± 1.6 s) than with MOLLI (18.3 ± 3.0 s) without visually perceivable impact on the reconstructed myocardial T1 maps. Figure .6 s thanRR [To exploit benefits of quantitative T1 mapping we sought to develop an accurate practical method characterised by a shorter breath-hold of the order of 10 seconds, which is easily achievable for patients. Figure RR  , fat (T1~200 ms), liver (~700 ms), skeletal muscle and myocardium ~1000 ms), blood (~2000 ms) and lymph or pericardial effusion (~3000 ms). ShMOLLI demonstrates robust T1 measurement properties across a wide range of T1 values and heart rates in simulation and phantoms. While both ShMOLLI and MOLLI slightly underestimate true T1 values, MOLLI shows prominent dependency on heart rate. An empirical correction for MOLLI has been proposed that addresses specifically the normal myocardial T1 values at 1.5T [00 ms, blExcluding any such corrections , the measurements of myocardial T1 by ShMOLLI at 1.5T are in good agreement with in-vivo data published in the literature , particuin-vivo material was to directly compare ShMOLLI performance with MOLLI over a wide range of clinically relevant scenarios. This included measurements in normal myocardium, following shortening of T1's as a result of contrast administration and T1 prolongation related to myocardial infarction. T1 measurements agreed in healthy controls within ± 17 ms noise boundaries for normal myocardium and after Gd administration. Our MI data is consistent with previously published reports [The purpose of the limited  reports ,9,13,20 Typically, the penalty for reducing the number of images collected for T1 reconstruction is increased variability within the resulting T1 maps. Our simulation and phantom measurements predicted the noise penalty for ShMOLLI to be as much as 61%. However, in-vivo T1 measurements by ShMOLLI showed noise penalty of only 14% (1.5T) and 18% (3T) as compared to MOLLI T1 s. The repetition error was 1.6% for both methods at 1.5T and only excluding the worst measurements brought out the expected noise advantage of MOLLI at 3T. We found that while MOLLI benefited from more samples for the majority of measurements, the higher SNR was bought at the cost of more prominent outliers, especially at 3T. This may be due to the ShMOLLI conditional processing acting as an error checker, but detailed analysis of such effects exceeds the scope of this work. Overall, for most of the T1 values tested, the in-vivo noise penalty for ShMOLLI due to a shorter imaging time is only 10-20%. We attribute this favourable observation mostly to the beneficial effect of the short breath-hold, which limits the incidence of breathing motion, estimated as the cause for 31% of image artefacts [The ShMOLLI technique holds promise for wider application of non-contrast T1-mapping towards cardiac conditions in which there are focal changes, such as myocardial infarction and myocarditis. It may be pivotal in studying conditions in which there are diffuse myocardial changes, such as chronic heart failure, hypertrophic cardiomyopathy and infiltrative diseases such as cardiac amyloidosis and sarcoidosis. The presented comparisons warrant the ongoing ShMOLLI deployment on its own merit in several more comprehensive patient validation studies.The novel ShMOLLI sequence for myocardial T1-mapping generates robust, high resolution quantitative T1 maps in agreement with published data in the literature in just 9 heart-beats across a wide range of heart rates and T1 values. Single short breath holds are typical for routine examinations to make them easily achievable for patients and permit wider clinical application of quantitative mapping. Implementation of nonlinear T1 fitting directly in the scanner image reconstruction pipeline yields immediate access to T1-maps for viewing, allowing for re-acquisition if necessary. In patients presenting with recent myocardial infarction, preliminary data demonstrates ShMOLLI superiority in distinguishing injured from normal myocardium, with areas of long T1 co-localizing with injured myocardium as assessed by LGE. ShMOLLI provides a valuable clinically applicable tool for myocardial tissue characterisation with or without the use of contrast agents.61/387,591: SKP, MDR and AG. SYSTEMS AND METHODS FOR SHORTENED LOOK LOCKER INVERSION RECOVERY (Sh-MOLLI) CARDIAC GATED MAPPING OF T1. September 29, 2010.US patent pending SKP provided the concept and implementation of the method, performed simulations, phantom measurements, data analysis and drafted the manuscript. VMF collected and processed data in normal controls and contributed very significantly to the drafting of the manuscript. EDA collected patient datasets. LEC helped with design of phantoms. AG contributed to the sequence implementation on the scanner. SN contributed to study design acting as the last author from clinical viewpoint. MDR contributed to the study concept, design, method implementation and the manuscript as last author. All authors read, commented or edited the manuscript, and approved the final version.


Diffuse myocardial fibrosis may be a fundamental features of adverse myocardial remodeling in idiopathic non-ischemic cardiomyopathy. As T1-weighted cardiac magnetic resonance (CMR) imaging provides an alternative method of diffuse fibrosis quantification, we sought to assess the association of myocardial T1 value to left ventricular reverse remodeling (LVRR).2 at 24 months. A multivariable logistic regression analysis was performed to identify associations with LVRR.We performed CMR in 24 patients with idiopathic non-ischemic cardiomyopathy  and also in 12 healthy volunteers as control subjects. T1 mapping was performed with post-contrast Look-Locker gradient echo. Baseline echocardiography as well as hemodynamic and metabolic data were collected at the time of CMR. Patients were followed over a median time of 8 months for LVRR which was defined as a left ventricular ejection fraction (LVEF) increase of ≥10 U and a decrease in indexed left ventricular end-diastolic diameter (LVEDD) of ≥10% or indexed LVEDD of < 33 mm/mLVRR was found in 8 patients (33%). Mean T1 value was substantially lower in patients without LVRR (240+26) compared to patients with LVRR  and healthy controls  (FigurePost contrast T1 value is a predictor of LV reversed remodeling in patients with idiopathic non-ischemic cardiomyopathy, independent of baseline LVEF and the presence of myocardial scar.None.