Left ventricular stroke area by transoesophageal echocardiographic automated border detection has been shown to be strongly correlated to left ventricular stroke volume. Respiratory variations in left ventricular stroke volume or its surrogates are good predictors of fluid responsiveness in mechanically ventilated patients. We hypothesised that respiratory variations in left ventricular stroke area (ΔSA) can predict fluid responsiveness.Eighteen mechanically ventilated patients undergoing coronary artery bypass grafting were studied immediately after induction of anaesthesia. Stroke area was measured on a beat-to-beat basis using transoesophageal echocardiographic automated border detection. Haemodynamic and echocardiographic data were measured at baseline and after volume expansion induced by a passive leg raising manoeuvre. Responders to passive leg raising manoeuvre were defined as patients presenting a more than 15% increase in cardiac output.p < 0.01). ΔSA decreased significantly in response to volume expansion . ΔSA was higher in responders than in non-responders . A cutoff ΔSA value of 16% allowed fluid responsiveness prediction with a sensitivity of 92% and a specificity of 83%. ΔSA at baseline was related to the percentage increase in cardiac output in response to volume expansion .Cardiac output increased significantly in response to volume expansion induced by passive leg raising (from 2.16 ± 0.79 litres per minute to 2.78 ± 1.08 litres per minute; ΔSA by transoesophageal echocardiographic automated border detection is sensitive to changes in preload, can predict fluid responsiveness, and can quantify the effects of volume expansion on cardiac output. It has potential clinical applications. Volume expansion is one of the most common manoeuvres to increase cardiac output (CO) in patients with circulatory failure. However, if inappropriate, volume expansion may have deleterious effects such as volume overload, systemic and pulmonary oedema, and increased tissue hypoxia . It is tStatic indicators of fluid responsiveness such as central venous pressure (CVP) and pulmonary capillary wedge pressure have been shown to be poor predictors of fluid responsiveness -6. In coTransoesophageal echocardiography is widely used in the operating room or in the intensive care unit for monitoring left ventricular (LV) systolic function and LV preload ,15 usingThis study was approved by the institutional review board committee , and all patients gave written informed consent. Twenty patients  undergoing coronary artery bypass grafting were studied. Exclusion criteria were cardiac arrhythmia, cardiac shunts, LV dysfunction (preoperative LV ejection fraction < 50%), and any contraindication to transoesophageal echocardiography.2O). Inspiratory-to-expiratory ratio was set to 1:2. Positive end-expiratory pressure was set between 0 and 4 cm H2O according to the attending physician.Anaesthesia was induced using propofol (1 to 3 mg/kg) and sufentanil (0.5 to 1.0 μg/kg), and orotracheal intubation was facilitated with pancuronium (0.1 to 0.15 mg/kg). After induction of anaesthesia, an 8-cm 5-French tipped catheter  was inserted in the left or right radial artery and a triple-lumen 16-cm 8.5-French central venous catheter was inserted in the right internal jugular vein . Pressure transducers  were placed on the mid-axillary line and fixed to the operation table to ensure their position at an atrial level during the entire protocol. All transducers were zeroed to atmospheric pressure before each step of the protocol. Thereafter, a 5-MHz transoesophageal multiplane transducer  was inserted in the patient's oesophagus. Anaesthesia was maintained with continuous infusions of propofol (5 to 8 mg/kg per hour) and sufentanil (0.7 to 1.0 μg/kg per hour) to keep a bispectral index  between 40 and 50. Patients were ventilated in a volume-controlled mode with a tidal volume of 10 ml/kg at a frequency of 12 to 14 cycles per minute : heart rate, systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, and CVP.Echocardiographic images were recorded using a Hewlett-Packard Sonos 2500  with automated border detection capabilities. The transoesophageal multiplane transducer was positioned to obtain a transgastric, cross-sectional view of the LV at midpapillary muscle level with the transducer positioned to obtain the image that had the most-circular overall geometry . The cromax) and minimal (PPmin) values of PP were determined over the same respiratory cycle. The respiratory variations in PP, ΔPP, were then calculated as described by Michard and colleagues. [max - PPmin)/([PPmax + PPmin]/2)] × 100%, and averaged over three consecutive respiratory cycles.Pulse pressure (PP) was defined as the difference between systolic and diastolic pressures. Maximal  and minimal (SAmin) values of PP were determined over the same respiratory cycle. ΔSA was then calculated using the same formula described previously to calculate ΔPP: [(SAmax - SAmin)/([SAmax + SAmin]/2)] × 100%  and the end-systolic area Figure  20]. Ma. Ma20]. LVEDA was defined as peak of the LV area during diastole. LVEDAI was defined as LVEDA/surface body area. For each measurement, an average of three consecutive cardiac beats throughout the respiratory cycle were evaluated.2. [CO was used to monitor an increase in stroke volume in response to volume expansion. CO was calculated using the velocity time integral (VTI) obtained by transoesophageal echocardiography from the transgastric long-axis view . VTI was2. ,28. The All patients were studied after induction of anaesthesia but before surgery. Haemodynamic and echocardiographic data were recorded during two consecutive steps. (a) The patient was studied in the semirecumbent position (45°) after a two minute period of haemodynamic stability. First, pulsed Doppler aortic flow was recorded from the transgastric long-axis view. Then, automated border detection data were recorded from a transgastric, cross-sectional view of the LV at midpapillary muscle level. (b) Using the automatic operation table, the patient's legs were raised to a 45° angle with the patient's trunk in a supine position. In this position, echocardiographic and haemodynamic data were recorded within two minutes. Automated border detection data were recorded before pulsed Doppler aortic flow. This sequence was chosen in order to keep the automated border detection settings stable between the two measurements because of a known dependency of automated border detection on echocardiographic gain settings. This protocol was chosen because of its demonstrated ability to mimic fluid challenge -32. MechU test. Receiver operating characteristic (ROC) curves were generated for CO, CVP, LVEDA, ΔPP, and ΔSA, varying the discriminating threshold of each parameters, and areas under the ROC curves were calculated and compared [p value less than 0.05 was considered statistically significant. All statistic analysis was performed using SPSS 13.0 for Windows .All data are presented as mean ± standard deviation. Changes in haemodynamic parameters induced by changes in loading conditions within the same group were assessed using a non-parametric Wilcoxon test. Spearman rank method was used to test linear correlation. Patients were divided into two groups according to the percentage increase in CO after the passive leg raising manoeuvre: responders were defined as patients presenting an increase in CO of more than or equal to 15%  and non-compared   were excluded because of poor echocardiographic images.p < 0.01). All haemodynamic parameters changed significantly in response to the passive leg raising manoeuvre (Table p < 0.05 for both)  and CVP increased from 3 ± 4 mm Hg to 18 ± 4 mm Hg (p < 0.01)  and an acceptable agreement between ΔSA and ΔPP (3% ± 5%) at baseline. ΔSA and ΔPP at baseline were significantly higher in responders than in non-responders , whereas neither difference in CVP  nor difference in LVEDAI  and CO  reached statistical significance between these two groups. The areas under the ROC curves (± standard error) were 0.910 ± 0.073 for ΔPP, 0.958 ± 0.043 for ΔSA, 0.271 ± 0.125 for CVP, 0.236 ± 0.114 for LVEDAI, and 0.431 ± 0.134 for CO . Difference in area under the curve between ΔSA and ΔPP did not reach significance (p = 0.83). The threshold ΔPP value of 12% allowed discrimination between responders and non-responders with a sensitivity of 92% and a specificity of 83%. The threshold ΔSA value of 16% allowed discrimination between responders and non-responders with a sensitivity of 92% and a specificity of 83% . ΔPP before volume expansion also showed a significant correlation to changes in CO , confirming previous results. In contrast, static indicators such as LVEDAI and CVP before volume expansion were not related to changes in CO in response to volume expansion   and displays the area as a calibrated waveform in real time. Several previous investigations have shown a strong relationship between cross-sectional LV area and LV volume ,23. MoreRecently published studies have shown that the passive leg raising manoeuvre was able to mimic volume expansion and to predict fluid responsiveness in mechanically ventilated patients ,32. ThesTransoesophageal echocardiography is widely used in the intensive care unit and in the operating room. It is now a well-established tool for intensivists and anaesthesiologists. It allows analysis of left and right ventricular functions and provides invaluable information for the management of patients with circulatory failure ,27. In tThe patients enrolled in this study underwent coronary artery bypass grafting and may have wall motion abnormalities. However, a study conducted in patients undergoing coronary artery bypass grafting demonstrated that even in this group of patients a linear correlation exists between changes in SA and stroke volume . Thus, wA limitation of this study is a possible artifact caused by a respiratory-related motion of the heart relative to a fixed echocardiographic probe. Brenner and colleagues  describeΔSA derived from transoesophageal echocardiographic automated border detection appears to be a non-invasive and reproducible index of changes in loading conditions, fluid responsiveness, and quantification of the effects of volume expansion on CO in mechanically ventilated patients. ΔSA has potential clinical applications.• ΔSA can be assessed using transoesophageal echocardiographic automated border detection in mechanically ventilated patients.• ΔSA is sensitive to changes in LV preload.• A ΔSA cutoff value of 16% allows discrimination between responders to volume expansion and non-responders.• The higher the ΔSA before volume expansion, the higher the increase in CO induced by volume expansion.• ΔSA is a simple tool for fluid responsiveness assessment using transoesophageal echocardiographic LV short-axis view.CO = cardiac output; CVP = central venous pressure; LV = left ventricle or left ventricular; LVEDA = left ventricular end-diastolic area; LVEDAI = left ventricular end-diastolic area index; PP = pulse pressure; ΔPP = respiratory variations in pulse pressure; ROC = receiver operating characteristic; SA = stroke area; ΔSA = respiratory variations in left ventricular stroke area; VTI = velocity time integral.The authors declare that they have no competing interests.MC conceived of and designed the study, performed analysis and interpretation of data, edited the manuscript, and gave final approval of the manuscript. JS performed analysis and interpretation of data, drafted the manuscript, and gave final approval of the manuscript. OD and FF performed analysis and interpretation of data and gave final approval of the manuscript. OB and J-JL revised the manuscript critically for important intellectual content, edited the manuscript, and gave final approval of the manuscript.


FDC may account for 20–48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures  and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed  Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by ventricular dilatation and impaired systolic function . DCM is idiopathic , when the disease appears sporadic, isolated in a single member of a family and without known cause, or familial when occurring in two or more related family members [DCM is defined as  members ,2.The diagnosis of DCM is made according to criteria provided by the World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) , the GuiDCM is defined by the presence of: a) fractional shortening (FS) less than 25% (> 2SD) and/or ejection fraction less than 45% (> 2SD); and b) left ventricular end diastolic diameter (LVEDD) greater than 117%  [affected , unaffected or unknown [major and minor criteria that have been developed to account for the high frequency of minor cardiac abnormalities within families with FDC and the need of more sensitive criteria [A familial DCM (FDC) is defined by the presence of: a) two or more affected relatives with DCM meeting the above criteria; or b) a relative of a DCM patient with unexplained sudden death before the age of 35 years . In FDC, unknown . This clcriteria .affected status is defined by the presence of: a) 2 major criteria consisting of left ventricular systolic dysfunction  and dilatation  [and one minor criterion; or c) 3 minor criteria. The unknown status is defined by the presence of 1 or 2 minor criteria and the unaffected status is defined by the presence of a normal heart or the determination of other causes of myocardial dysfunction.In relatives, the Minor criteria of disease are: a) unexplained supraventricular arrhythmias , or frequent (> 1000/24 h) or repetitive (3 or more ectopic beats with a heart rate > 120 beats/min) ventricular arrhythmias before the age of 50; b) left ventricular dilatation ; c) left ventricular dysfunction ; d) unexplained cardiac conduction system disease ; e) unexplained sudden death or stroke before 50 years of age; f) segmental wall motion abnormalities  in the absence of intraventricular conduction defect or ischemic heart disease.Exclusion criteria for idiopathic/familial DCM are: a) blood pressure more than 160/110 mmHg, documented and confirmed through repeated measurements; b) obstruction (more than 50%) of a major branch of the coronary artery; c) alcohol intake more than 100 g/day; d) persistent high rate supraventricular arrhythmia; e) systemic diseases; f) pericardial diseases; g) congenital heart diseases; h) cor pulmonale; j) myocarditis.DCM can be distinguished from other forms of secondary dilatation and dysfunction of the ventricles due to known cardiac or systemic processes . These aTable DCM has a prevalence of one case out of 2500 individuals  with an familial DCM [Prior to 1990, FDC was not widely recognized and genetic contributions to the development of dilated cardiomyopathy were rarely implicated in disease models. In 1981, a retrospective review of 104 patients with DCM at the Mayo clinic estimated that approximately 2% of cases were potentially familial in nature . More relial DCM . Unfortudystrophinopathy at the skeletal muscle biopsy [Patients initially present with signs and symptoms of heart failure, due either to volume overload or to low cardiac output. Usually, by the time of the diagnosis, probands  have severe impairment of the left ventricular ejection function and are in New York Heart Association (NYHA) functional class III-IV. Affected relatives, on the other hand, can be asymptomatic with mild ventricular dilatation and dysfunction. Twenty to thirty-five percent of patients present with chest pain, mostly during exercise, and the electrocardiogram (ECG) may show pseudo-infarction Q waves. Angina pectoris is thought to be due to limited coronary vascular reserve. Fatigue is present in almost one third of patients. Palpitations are very common, due to ventricular arrhythmias, nevertheless, syncope and sudden death rarely constitute the first symptom of the disease. Pulmonary and systemic thromboembolisms occur, as first manifestation of the disease, at a rate of 1 to 6% per year. Most of them can be found in cases with severe left ventricular dilatation and dysfunction. A particular form of familial DCM due to mutation of the lamin A/C gene ,15 presee biopsy -19.DES, DMD, LMNA, MYBPC3, MYH7, TAZ, TNNT2, and TMP1 .The basic evaluation in the proband  consistsIn FDC, there is clear evidence of Mendelian segregation of disease phenotype. FDC is a heterogeneous entity Table . Differesporadic or truly "idiopathic" DCM ), the contribution of FDC gene mutations to isolated or sporadic dilated cardiomyopathies is not well-defined.Carefully designed studies of larger FDC families  have implicated 29 chromosomal loci as containing FDC genes. Several different genes at these loci have been identified to date  inhibitors reduce mortality, hospitalization and progression of heart failure, as noted in several trials including CONSENSUS [• ONSENSUS , SOLVD [ONSENSUS , and SAVONSENSUS . These dAngiotensin receptor blockers (ARBs) provide a reasonable alternative to ACE inhibitors (in patients who are intolerant to these agents). The use of ARB is based on trials such as ELITE-I and II [• I and II , Val-HeFI and II , and OPTI and II . The dosFirst generation calcium channel blockers are not recommended in heart failure patients.• endothelin antagonists have been disappointing to date and these agents are not recommend in standard guidelines [• Trials using idelines .Diuretics have not been assessed in a randomized study to verify their effect on survival in heart failure. Furosemide is used at daily doses of 20 mg to 600 mg daily. Bemetanide and ethacrynic acid are other loop diuretics currently in use. Torsemide has better bioavailability when taken orally and is used in some patients who do not respond to oral furosemide. Frequently, the dose is half of that of furosemide for a similar effect. When high doses of loop diuretics are needed and, especially if the patient has diuretic resistance, metolazone is added, usually at a dose of 2.5 mg once/day to 5 mg twice/day. Acetazolamide is used at a dose of 250 to 500 mg daily in some patients with metabolic alkalosis.• Aldosterone inhibitors such as spironolactone and eplerenone reduce mortality, as noted in RALES [• in RALES  and EPHEin RALES , respectVasopressin antagonists are still under investigation.• Natriuretic peptides are available only intravenously for acute decompensation.• inotrope, which use is widely accepted in chronic heart failure, is digoxin. It is dosed at 0.125–0.25 mg once/day and is adjusted to renal function. A recent post-hoc analysis of the Digitalis Investogators Group [• The only rs Group  divided Beta-adrenergic blockers are considered a major advance in the therapy of heart failure. CIBIS-II [• CIBIS-II  and MERICIBIS-II  showed aCIBIS-II . Beta-blanticoagulants/antiplatelet agents is a controversial subject and more studies are underway to identify which therapy to use and in whom. In clinical practice, anticoagulation is often used in patients with a left ventricular ejection fraction less than 30%.• The use of The use of cardiac resynchronization therapy (CRT) with biventricular pacing improves symptoms in advanced heart failure and reduces hospitalizations and mortality. In the COMPANION trial  CRT reduFinally, patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant. In this setting, heart transplantation improves survival and quality of life.So far, no trials exist on the usefulness of therapy in asymptomatic affected relatives. However, based on studies on ischemic heart disease, it is believed that an early use of ACE inhibitors and/or beta adrenergic blockers could be very important in slowing the progression of the disease.Genetic counseling approaches for familial FDC are still under-developed and consensus guidelines are lacking. The high degree of genetic heterogeneity, uncertainty as to which familial DCM genes are commonly mutated, and the propensity to uncover private mutations, have combined to hinder the development and widespread application of clinical testing. As the disease is of relatively late onset, many individuals in older generations may be unavailable for examination or may be deceased. Limited knowledge of FDC and thorough evaluation of relatives at risk by practicing generalists and cardiologists likely also contributes to under-recognition of this condition.An accurate family history and screening of first-degree relatives has fundamental importance in FDC. This approach is not yet widely practiced in the United States. Each first-degree relative should undergo a detailed physical examination, ECG, and echocardiogram. Serum creatinine kinase levels can also be useful, especially if the proband has elevation of this marker. Signal averaged electrocardiography (SAECG) has also been suggested as an additional diagnostic tool . The thoincreased risk of developing FDC for mutation carriers, rather on models that implies a certainty of disease for all mutation carriers.For families where a pathogenetic mutation has been detected, the evaluation of relatives at risk can include molecular testing to confirm the presence or absence of the pathologic mutation. This information can be integrated into the genetic counseling provided to each individual within that family. Non-carriers may be reassured that they are not at increased risk of developing FDC. Asymptomatic carriers who are at increased risk of disease may be considered for regular evaluations (including echocardiogram) to screen for the development of early disease. As incomplete penetrance is a feature of this disease, the counseling session of asymptomatic mutation carriers should focus on the In families where a pathologic mutation has not been detected, genetic counseling is understandably less precise. A detailed examination and analysis of the pedigree is essential to define, if possible, the likely mode of inheritance. Implicit in this exercise is that historical information provided about relatives should be confirmed through either direct evaluation of relatives or reviewing medical records and/or autopsy reports. In performing the genetic counseling, careful attention to the problems of age-dependent and incomplete penetrance should be integrated into the discussion. Relatives judged to be at significantly increased risk of developing a cardiomyopathy should be considered, as above, for regular screening.The use of molecular genetic testing to test fetuses for adult-onset disease has been the subject of a number of ethical discussions. In spite of initial widespread reluctance to embark upon testing in this setting, a number of recent examples are challenging this paradigm. Such discussions are likely to ensue in the context of familial DCM once clinical genetic testing and counseling becomes more widely available.There are many aspects of familial DCM that remain poorly understood. A clear and comprehensive understanding of the genetic epidemiology of gene mutations in both FDC and sporadic DCM is needed. Such knowledge will provide a foundation for the development and continued improvement of genetic testing, which will likely be panel-based to simultaneously test multiple genes. Animal models of FDC have been developed to better characterize the pathogenesis of how the underlying genetic defects initiate and/or propagate the disease process. Ultimately, this work may suggest novel approaches to target the underlying molecular defects. There is evidence of substantial variability in phenotype within families, suggesting that environmental and/or modifying genetic factors may interact with the underlying FDC mutations. Pilot studies to explore these hypotheses are now underway. Finally, experimental approaches to explore how conventional cardiovascular therapies impact the disease process are desperately needed.


Cardiovascular risk associated with diabetes may be partially attributed to left ventricular structural abnormalities. However, the relations between left ventricular structure and diabetes have not been extensively studied in African-Americans.We studied 514 male and 965 female African-Americans 51 to 70 years old, in whom echocardiographic left ventricular mass measurements were collected for the ARIC Study. In these, we investigated the independent association of diabetes with left ventricular structural abnormalities.Diabetes, hypertension and obesity prevalences were 22%, 57% and 45%, respectively. Unindexed left ventricular mass was higher with diabetes in both men  and women , respectively. Prevalence of height-indexed left ventricular hypertrophy was higher in women while increased relative wall thickness was similar in men and women. Those with diabetes had higher prevalences of height-indexed left ventricular hypertrophy , and of increased relative wall thickness . Gender-adjusted associations of diabetes with left ventricular hypertrophy (OR = 2.29 95%CI:1.79–2.94) were attenuated after multiple adjustments in logistic regression (OR = 1.50 95%CI:1.12–2.00). Diabetes was associated with higher left ventricle diameter (OR = 2.13 95%CI:1.28–3.53) only in men and with higher wall thickness (OR = 1.89 95%CI:1.34–2.66) only in women. Attenuations in diabetes associations were frequently seen after adjustment for obesity indices.In African-Americans, diabetes is associated with left ventricular hypertrophy and, with different patterns of left ventricular structural abnormalities between genders. Attenuation seen in adjusted associations suggests that the higher frequency of structural abnormalities seen in diabetes may be due to factors other than hyperglycemia. Left ventricular hypertrophy (LVH) is frequent in diabetic patients ,2. and hper se, may explain much of the association seen between diabetes and LV structural abnormalities.Alterations in left ventricular (LV) structure have been linked to diabetes but also to a large number of related conditions such as aging, hypertension, obesity, central obesity, dyslipidemia, salt intake, and physical inactivity -7 Hence,African-Americans have a high prevalence of left ventricular structural abnormalities  and of iThis study evaluates the independent cross-sectional associations of diabetes with LV structural alterations in a community-based sample of African-Americans with a high prevalence of other known risk factors for LVH.The ARIC Study is a prospective study designed to investigate the etiology and natural history of CVD in four U.S. communities. The study design and procedures, including the echocardiography protocol, have been previously reported ,15. Betw2. Body surface area (BSA) was calculated as BSA = 0.007184 * weight [kg]0.425 * height [cm]0.725, according to the Dubois formula [Diabetes was defined as a participant report of physician diagnosis or diabetic medication use, fasting glucose ≥ 126 mg/dL, or casual glucose ≥ 200 mg/dL. Hypertension was defined as a mean of two separate measures greater than 140/90 mmHg or antihypertensive drug use. Obesity was defined as a body mass index ≥ 30 kg/m formula . Waist-h2.7, with a boundary of 51 g/m2.7 to define LVH in both genders [The two-dimensional guided M-mode echocardiographic tracings were acquired with an Acuson 128XP/10c System. Images were digitized and analyzed off-line with a commercially available program. Only frames with optimal visualization of interfaces that simultaneously showed the interventricular septum, LV internal diameter, and posterior wall were used for readings. Tracings were read by one of two cardiologists, unaware of subject's clinical data, and the average value from 3 measurements was computed. LV mass was calculated using M-mode tracings according to American Society of Echocardiography conventions  and Deve genders . The int genders .Alterations in LV geometry were assessed by several approaches. Relative wall thickness (RWT) was calculated as the sum of wall thicknesses  divided by LV diastolic diameter, with elevated RWT defined as greater or equal to 0.45 ; In multWe investigated the differences in crude prevalences between groups in stratified analyses with Chi-square statistics. We used logistic regression analysis  to study the independent association of variables with pre-defined echocardiographic features. Associations were adjusted for adiposity by including obesity, defined by BMI, and waist-hip ratio in models. For further, in multiple adjustment, we added the covariates age, systolic blood pressure, antihypertensive medication use, total cholesterol, activity level, smoking and education level. Height was also included as a covariate in analyses of increased LV diameter and increased wall thickness. In these multivariable models, we used clinically defined cut-points, when present, for continuous exposure variables. In order to produce exposure frequencies similar to that of diabetes, we modeled variables without pre-defined cut-points comparing the upper quartile to the lower three. Gender interactions were tested using the Wald statistic of the gender interaction term. We employed the variance inflation factor to identify collinearity among variables measuring potentially similar biological effects. The variance inflation factor was never greater than 3.0, suggesting that important collinearity was absent .The 1479 individuals included in the study differed somewhat from the 955 subjects undergoing the exam but excluded from these analyses. The included participants had a similar gender distribution, somewhat lower prevalences of diabetes  and obesity , and less hypertension  than those excluded.2.7 vs. 46.5 ± 13.2 g/m2.7, p < 0.01; women:55.2 ± 17.0 g/m2.7 vs. 47.2 ± 13.5 g/m2.7, p = 0.001).Of those studied, 514 (35%) were men and 965 (65%) were women. Compared with men, women had considerably higher prevalences of diabetes, obesity and hypertension , obesity , and hypertension . Prevalences of increased RWT were also greater in those with diabetes  and hypertension , but not so in those classified as obese . However, sex-specific analyses showed that differences in prevalences of height-adjusted LVH associated with diabetes were similar in men and women, but the higher prevalence of increased RWT with diabetes was seen only in women  and women . Multiply-adjusted gender-specific analyses revealed that diabetes was associated with increased RWT in women (OR = 1.63 95%CI 1.12–2.37) but not in men (OR = 0.64 95%CI 0.39–1.04).th quartile vs. the rest, OR = 3.43 95%CI 2.42–4.87) and wall thickness (OR = 1.68 95%CI 1.27–2.23); in men, with greater wall thickness (OR = 2.58 95%CI 1.63–4.07).Gender differences in RWT response were additionally investigated evaluating the RWT components – increased LV diameter and sum of wall thicknesses Table . MultiplConsistent with previous reports ,9, LV stEmployment of relative wall thickness to evaluate geometric remodeling resulted in an unanticipated finding. Whereas RWT prevalences were similar between men and women, diabetes was associated with increased RWT in women; in men, if anything, with the reverse. Separate evaluation of the components of relative wall thickness – ventricular chamber size and wall thickness – produced a possible explanation for the apparent paradox: In women diabetes was associated with increased wall thickness, but not with increased left ventricular diameter. In men, on the contrary, diabetes was more strongly associated with increased left ventricular diameter than with increased wall thickness. This finding demonstrates a potential limitation of using the ratio of these two measures to identify the structural changes related to diabetes.Differences in correlates of left ventricular structure may indicate that the pathophysiologic mechanisms leading to heart maladaptive response differ somewhat between genders. Females have been found to have an increased wall thickness response to pressure overload compared with males in clinical  and in aThe traditional explanation for the important association of obesity with abnormal LV responses is that obesity produces a hemodynamic stress, with increased heart rate, blood volume, and blood pressure . HoweverThere are, however, additional specific mechanisms by which diabetes might be related to LV geometry and hypertrophy. Diabetes may contribute to ventricular adaptive changes through an increase in pro-inflammatory immune mediators resulting from the oxidative stress caused by hyperglycemia ,35. The Some limitations to our study merit mention. Forty percent of the initially enrolled participants could not be analyzed, creating the possibility of selection bias influencing our results. In this regard, as those included were generally healthier than those excluded, and the associations we have demonstrated may underestimate the true association between diabetes and LVH. The high prevalence of obesity makes these results of questionable generalizability to leaner populations. Finally, the high prevalence of examined echocardiographic features results in the reported odds ratios being overestimates of relative risk.per se. Diabetes associated altered ventricular structure appears to differ by gender. This may be due to gender difference in the cardiac response to the pathophysiologic factors underlying LV morphology – in men the process of increased mass being more coupled with chamber dilation whereas in women expressed mostly as wall thickening. The gender difference in LV structure complicates the use of common geometric patterns definitions when comparing ventricular remodeling in response to diabetes.In conclusion, diabetes is associated with increased LVH in middle-aged and elderly African-American men and women. Most of this increase appears to be more closely associated with obesity, especially central obesity, than to diabetes The author(s) declare that they have no competing interests.MF and BBD designed and performed the statistical analysis and drafted the manuscript. All authors helped with suggestions in analysis and manuscript, read and approved the final manuscript.


This review article summarizes the results of histopathological studies to assess heart failure in humans. Different histopathological features underlying the clinical manifestations of heart failure are reviewed. In addition, the present role of echocardiographic techniques in assessing the failing heart is briefly summarized. Any cardiac disease may end in congestive heart failure (CHF), including coronary heart disease. Since mortality has been reduced in acute coronary syndromes, the latter will be the main condition resulting in CHF. This concept stimulated a systematic, quantitative study in 144 hearts with irreversible insufficiency excised at transplantation compared with 144 hearts without CHF both from patients and normal subjects dead from accident .Our 144 patients with irreversible CHF included 63 with chronic coronary heart disease, 63 with dilated cardiomyopathy and 18 with chronic valvular heart disease. All had a similar clinical pattern. The advantage is that surgically excised hearts are free of any change which may occur in the terminal, agonic phase and interfere with other autoptic findings.The main data supporting this review are synthesize in Table This variable assumes a central pathogenic meaning since it results (ischemia → continuous infarct expansion → scar) in fibrous, non contracting myocardium ending in progressive insufficiency. In all the three conditions examined, the extent of myocardial fibrosis Figure  was unabIn dilated cardiomyopathy the etiopathogenetic hypothesis is that a chronic virus myocarditis resulting in myocardial fibrosis explains this pathologic condition. Both myocardial fibrosis, as already mentioned, and lymphocytic infiltrates, as expression of a virus infection, showed a too low frequency and extent. In particular the number of lymphocytic foci was less than controls in all the insufficient hearts, with a number of elements per focus less than 20. Only in "silent" Chagas patients [apparently healthy subjects serum-positive for this disease who died suddenly and unexpectedly] an extensive lymphocytic myocarditis associated with catecholamine necrosis was observed.A clinical study has shown that ischemic episodes are not part of CHF . On the This genomically programmed cell death, supposed to be triggered by many risk factors, has been recently advocated to explain different cardiac pathologies in which apoptosis has been indirectly "demonstrated" by TUNEL techniques . This neThe weight/size paradox i.e. heavy heart weight with both cardiac wall and myocyte normal thickness is explained by dilatation of heart chambers with lengthening by distension of myocardial cells resulting in normal wall thickness. Such a stretch of myocytes does not occur  as shownBy cardiac hypertrophy we mean a tridimensional augmentation in number of myofibrils and other components of myocardial cells to compensate an increase of heart work. The myocyte hypertrophy results in a heavy cardiac weight. When insufficiency begins the weight/size paradox can not be explained by longitudinal division of myocytes never demonstrated or by neogenesis of myocytes -10, a coTo explain the paradox, the other well granted hypothesis is that an interpenetration of myocytes may reduce the cardiac wall thickness. First, such never proved interpenetration may explain the latter and dilatation of heart cavities Figure . HoweverThis assumption has a confirmation in the high frequency of catecholamine necrosis  even if The first conclusion is that the pooling of all items of the quoted consensus has no support from morphopathology, but neurohormonal activation which, per se, does not explain congestive failure rather an adrenergic stress prevented by beta-blocking therapy. However, the following two findings not mentioned in this consensus are the following.This non ischemic lesion  is typicThis change is worthy of mention to avoid any confusion with embologenic endocardial thrombosis. The presence of the latter was 21% in coronary heart disease, 10% in dilated cardiomyopathy and 6% of valvulopathic patients with CHF. Most of these endocardial thrombi were organized. Myoelastofibrosis was demonstrated in 98% of congestive hearts being present also in controls Table , followeThough various imaging techniques have been introduced for assessing left ventricular function, echocardiography still represents the main choice in the clinical arena due to its unique combination of safety, feasibility, and reliability Table . Both diDoppler echocardiography traditionally allows diastolic abnormalities affecting overall cardiac function to be easily detected on routine examination. Inversion of the E/A ratio and prolongation of deceleration time on the transmitral flow pattern represent the first abnormalities which are encountered in the minor stage of diastolic dysfunction. A restrictive filling pattern, reflecting an increased pulmonary capillary pressure, is observed in case of more severe dysfunction and is associated to adverse outcome . More reThe clinical role of echocardiography for evaluating diastolic function is quite different depending on whether global left ventricular (LV) systolic function is preserved or not. In patients with preserved systolic function, measurement of transmitral flow in combination with mitral annular tissue Doppler velocities provide the most efficient means of assessing LV diastolic function and filling pressures. However, in case of global systolic dysfunction and accompanying diastolic dysfunction, the principal aim of Doppler echocardiography is to estimate filling pressure, which has known therapeutic and prognostic implications . In thesInitially described in studies including contrast or radionuclide ventriculography, global and regional left ventricular function are optimally assessed with echocardiographic technique in both resting and stress condition. With the ultrasound beam directed perpendicularly to the myocardium, wall motion and thickening can easily be detected on the imaging plane. Several imaging windows, including parasternal, apical, and subcostal views, are used to visualize all ventricular walls. More recently, three dimensional (3D) echocardiographic images are generated by integration of information from multiple 2D imaging planes. In addition, the introduction of harmonic imaging and the use of echocardiographic contrast media for improved endocardial border definition have significantly improved image quality, thereby enhancing the accuracy of assessment of left ventricular function particularly in patients with poor acoustic windows. Estimation of the LVEF by 2D echocardiography can be done either qualitatively by visual inspection of global and regional function or quantitatively, using geometric assumptions regarding the shape of the LV cavity.Global and regional LV systolic function can both be qualitatively and quantitatively assessed with echocardiography.Global function is qualitatively described as normal, depressed, or hyperdynamic. Although a comprehensive quantitative assessment of LV end-systolic and end-diastolic data would be ideal, such an approach is currently impractical for routine evaluation. Several quantitative approaches have been described, with Simpson's rule (disk-area method) being the most accurate for LV volume measurement and for computation of derived values such as LV ejection fraction . PerhapsThe regional assessment of LV systolic function is assessed by dividing the entire left ventricle into segments. The most popular models recommend the use of 16 or 17 segments ,16. A sc3D technique and myocardial strain imaging.Future developments for the assessment of ventricular function with echocardiography include the use of 3D echocardiography offers the theoretical advantage to provide incremental benefit over 2D techniques in terms of accuracy and reproducibility and appears to produce estimation of LV ejection fraction similar to radionuclide ventriculography and cardiovascular magnetic resonance -21.The term "strain" refers to an object's fractional or percentage change from its original dimension ,23, thus+2 from troponin-tropomyosine complex. The metabolic error could stimulate an abortive hypertrophy with elongation of myocytes by new sarcomeres with normal length without tridimensional myofibrillar iperplasia [The cause of CHF is still unknown, with the impression, based on morphopathologic data, that its pathogenesis consists in a primary metabolic error of myocytes which lost their ability to relax in the contraction cycle. At ultrastructure these elements are in contraction and this finding may indicate the inability to remove Caerplasia ,4.The author(s) declare that they have no competing interests.GB conceived and drafted the manuscript. RG and LC critically revised and helped to draft the manuscript. All authors read and approved the final manuscript.


Diabetes is associated with a cardiomyopathy that is independent of coronary artery disease or hypertension. In the present study we used in vivo magnetic resonance imaging (MRI) and echocardiographic techniques to examine and characterize early changes in myocardial function in a mouse model of type 1 diabetes.Diabetes was induced in 8-week old C57BL/6 mice with two intraperitoneal injections of streptozotocin. The blood glucose levels were maintained at 19–25 mmol/l using intermittent low dosages of long acting insulin glargine. MRI and echocardiography were performed at 4 weeks of diabetes (age of 12 weeks) in diabetic mice and age-matched controls.After 4 weeks of hyperglycemia one marker of mitochondrial function, NADH oxidase activity, was decreased to 50% of control animals. MRI studies of diabetic mice at 4 weeks demonstrated significant deficits in myocardial morphology and functionality including: a decreased left ventricular (LV) wall thickness, an increased LV end-systolic diameter and volume, a diminished LV ejection fraction and cardiac output, a decreased LV circumferential shortening, and decreased LV peak ejection and filling rates. M-mode echocardiographic and Doppler flow studies of diabetic mice at 4 weeks showed a decreased wall thickening and increased E/A ratio, supporting both systolic and diastolic dysfunction.Our study demonstrates that MRI interrogation can identify the onset of diabetic cardiomyopathy in mice with its impaired functional capacity and altered morphology. The MRI technique will lend itself to repetitive study of early changes in cardiac function in small animal models of diabetic cardiomyopathy. The existence of diabetic cardiomyopathy, a myocardial disease associated with diabetes in the absence of coronary artery disease, hypertension or any other known cardiac disease, is supported by evidence accumulated from a large and expanding literature -4. AbnorMice are increasingly used in diabetes research mainly because of the ability to create genetically engineered mice for investigation of the molecular mechanisms underlying cardiovascular complications -19. ChemThe purpose of the present study was to use MRI techniques to examine the early onset of myocardial dysfunction in STZ-induced diabetic mice. These studies can then be applied to interventions that may alter or prevent the onset of this condition using the advantage of repetitive examinations over selected periods of time.6–8 week old C57BL/6 female mice were obtained from Harlan  and housed at the MRI animal facility. All animals had free access to standard laboratory chow and water. Animal protocols were approved by the local Institutional Animal Care and Use Committee.Mice were injected intraperitoneally with 100 mg/kg of STZ  or vehicle once a day for two consecutive days. Tail blood glucose (TBG) levels were measured using a glucose oxidase test strip . Animals were considered to be diabetic if their TBG is > 13 mmol/l. The blood glucose levels and body weight of all mice were monitored biweekly. When their TBG is > 22 mmol/l, they were given intermittent low dosages of long acting insulin glargine  to maintFor MRI studies, mice were anesthetized with inhaled isoflurane (1.5% at 1 L/min oxygen flow) via a nose cone. During the experiment, the mouse was positioned supine on a nonmagnetic warming pad to maintain constant body temperature throughout the MR study.te = 4.0 ms, tr = 100 ms, and a flip angle, θ = 85°–90° was used for all experiments. The heart was initially positioned by measurement to the center of the magnet and then further set by observing the position using fast imaging with steady state precession (FISP) [te = 4.0 ms and tr = 50 ms was used to acquire single slice images in all three  planes. The slice position for the cine was set using this pilot scan. For cine and volume imaging a field of view, FOV = 2.56 × 2.56 cm was chosen and 256 each of phase encode and read steps were used to resolve the spatial distribution of excited spins. The image was made after zero filling in each direction to 512 × 512. Window functions were not used and some minor image quality enhancement may be achieved if window functions are used. For our purpose the signal contrast of the myocardium and "white" blood was sufficient to allow calculation of the relevant parameters.Experiments were performed on a 7 Tesla MR scanner . For cardiac imaging the gradient echo sequence  with te n (FISP)  as the aP, of mice used in these studies ranged from ~120–180 ms, and a respiratory rate of ~18–30 bpm. Trigger delays, td, were incremented at the spectrometer hardware in a chosen number of steps, nsteps, (nsteps = 10) according to td = (P-(P/nsteps))/P, where period is the time between the peaks of the R wave in the ECG trace. The images at each increment of the period were combined and displayed by cine in the mid-ventricular short axis slice. These provided data for assessment of left ventricular (LV) systolic and diastolic dynamics, and for calculations of fractional circumferential shortening and wall thickening after measuring the endocardial circumferential length and myocardial wall thickness at end diastole and end systole.Spectrometer triggering with combined respiratory and ECG triggers was used in all experiments. Thus, all MRI data are adjusted to accommodate for rate changes and the data are reflective of the ambient cardiac function and rate. The cardiac period, For volume calculations, a new set of images were collected with the slice position advanced by the slice thickness of 1.0 mm. In order to reduce the time that multi-slice experiments fit in to the repetition time (Tr) used for single slice experiments, the slice thickness was increased to 1.25 mm. Thus, in this case, the resolution in the slice shifting is compromised by 0.25 mm at most, and contributes an error of about 0.1% in total volume calculations compared with a 1 mm slice thickness. The total blood volume at end diastole and end systole was estimated by taking the sum of all cavity slice volumes assuming a uniform thickness of excitation across a chosen slice at the two trigger points.For LV blood volume measurements, endocardial borders were manually delineated. An independent observer was used whenever a questionable or indistinct image was encountered. These measurements rarely changed the summed data obtained from a given data acquisition. The end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated as the sum of all cavity slice volumes at end diastole and end systole. For assessment of LV systolic and diastolic dynamics, the cavity slice volume was measured in all acquired images and was plotted against the time from onset of the QRS trigger, and a volume-time curve was established. Peak ejection rate and peak filling rate were calculated from the maximum slopes of the LV ejection and filling curve .M-mode/Doppler echocardiography was performed using a 13 MHz 15L8 probe and an Acuson Sequoia 256 echocardiography system . The wall and cavity dimensions during diastole and systole were determined from long-axis views of the left ventricle . The mitFrozen and thawed mitoplasts from hearts were diluted into 10 mmol/l 3-(N-morpholino)propane-sulfonic acid (MOPS), 25 mmol/l KCl at pH 7.4 to a final concentration of 50 μg/ml . NADH oxt test was used to make comparisons between control and diabetic groups. Significance was ascribed to P values < 0.05.Data are expressed as mean ± SEM. An unpaired 2-tailed Student The mice generally developed significant elevation of blood glucose within a week following STZ injection Figure . The STZP < 0.001). Diabetic mice also showed significant thinning of the LV wall compared to control animals both at end diastole  and at end systole   Table .The heart rates were similar between diabetic and control mice (446 ± 11 vs. 470 ± 11 bpm). To determine the effects of diabetes on LV systolic function, the LV blood volumes were measured from multiple short-axis slices that cover the whole heart at end diastole and end systole. The EDV was not significantly changed after 4 weeks of diabetes (44.8 ± 1.0 vs. 46.0 ± 1.1 μl). The ESV, on the other hand, was increased by 23%. Therefore, a significantly reduced myocardial contractile function was observed in diabetic mice. The stroke volume, ejection fraction and cardiac output were decreased by 20%, 18% and 16%, respectively. A similar decrease in LV fractional circumferential shortening was also seen in diabetic mice (Table P < 0.05) and filling rate  indicating a decrease of both contraction and relaxation . Complex I is the rate limiting step in electron transport chain. Therefore this decrement is, in part, responsible for the observed loss in NADH oxidase activity. Other deficits that contribute to the diabetes-induced declines in electron transport are under investigation.To begin to assess the effects of diabetes on mitochondrial function, NADH oxidase activity, a measure of overall electron transport, was determined in mitoplasts prepared from hearts isolated from control and diabetic (4 weeks) mice. As shown in Figure It has been difficult in obtaining sequential analyses of early diabetic cardiomyopathy in humans, and even in small animal models. The cardiac phenotype of diabetic mice has been examined using in vivo and ex vivo techniques in both type 1 and type 2 diabetic mouse models -19,21-23Transthoracic echocardiography is a noninvasive method for in vivo assessment of cardiac function. It is readily available and very useful for serial studies on age-dependent cardiac changes ,39. M-moMRI provides accurate, reproducible, noninvasive 3-dimensional representations of cardiac structure and function. The MRI techniques have been adapted and validated to assess mouse cardiac function in vivo -28. UnliIn preliminary studies, we examined one marker of the onset of mitochondrial dysfunction (NADH oxidase activity) and demonstrated this parameter was decreased by 50% at 4 weeks. This translates into a significant deficiency of mitochondrial electron transport and serves as one of several indicators of an impaired cardiac energy state in early diabetes. These data help confirm a metabolic basis for the observed impairment of cardiac function using MRI interrogation. Mitochondrial dysfunction has been reported in the diabetic heart ,42. Such31P spectra provide the only noninvasive method to quantitate myocardial high-energy phosphates . This novel technique should prove complementary to standard MRI interrogation to study the contribution of altered energy metabolism to the development of diabetic cardiomyopathy. The major drawback at present is the design of appropriate small coils that will permit accurate localization of data to the myocardium separate from the underlying blood.Recently, MR spectroscopy has been used in mice to examine myocardial energy metabolism ,43. 31P Despite its advantages, MRI has limitations. It is costly, time consuming, has blood flow and motion generated artifacts, and has limited availability. Application of sensitive, discriminate software to minimize manual determination of selected cardiac parameters such as cardiac borders in repetitive slices will decrease the time required for analysis. We have found that the time required for positioning and acquisition of the relevant data was significantly decreased with experience of the personnel.In summary, we have implemented a noninvasive MRI technique that was used for the first time to detect and characterize the early onset of myocardial dysfunction in a mouse model of type 1 diabetes. This provides a powerful approach to examining early cardiac dysfunction in vivo in mice with transgenic manipulation or pharmacological interventions that will ultimately lead to a better understanding of the pathophysiology and to reduction of the incidence of diabetic cardiomyopathy in humans.The author(s) declare that they have no competing interests.XY and DCK conceived the study, participated in its design and coordination, performed and analyzed the data with statistical analysis and drafted the manuscript. RAT participated in the design of the study, provided expertise and oversight in the MRI procedures and helped with manuscript preparation. YAT and AA carried out the MRI data acquisition and helped with data analysis and manuscript preparation. SH and MWG carried out the diabetes induction and mouse maintenance. EP and SC carried out the echocardiography and data collection, and helped with data analysis. SM performed the mitochondrial assay, and LIS helped with data interpretation and manuscript preparation. BEG supervised the mouse maintenance and assisted with data analysis. All authors read and approved the final manuscript.


Histology, the study of how cells are organized into tissue, is a keystone of the biological sciences. For decades, histologists have depended upon methods such as the tried-and-true slides of stained tissue sections. Although much has been learned through these methods, how much more would be learned if histologists could view tissues in three dimensions?Today this advance is becoming a reality thanks to a newly developed ability to combine ultra–high resolution/microscopic computed tomography (microCT) scans with high-tech computer protocols to produce detailed 3-D images of mouse embryos. Besides the marked advantage of a 3-D perspective, the technique also achieves improvements in resolution, time required, and costs for studying developmental patterning effects attributable to genetically engineered mutations and chemically induced embryotoxicity.PLoS Genetics in April 2006.The research team that reported the development of this method, known as microCT-based virtual histology (MBVH), was led by Charles Keller, an assistant professor of cellular and structural biology at the Children’s Cancer Research Institute, University of Texas Health Sciences Center at San Antonio. The innovative technique was reported in Mouse embryos are commonly used to study gene function. The team’s original aim was to develop a method for rapidly assessing birth defects associated with targeted disruptions of each gene in the mouse embryo. According to the authors, this called for “systematic, interdisciplinary approaches to analyzing patterning defects in the mouse embryo.”What emerged, the authors wrote, was a “novel, rapid, and inexpensive method for obtaining high-resolution virtual histology for phenotypic assessment of mouse embryos.” Besides determining how genetic polymorphisms may contribute to end points such as birth defects and cancer, this new technique can perhaps be used to assess the safety of new medicines and other chemicals.The traditional method used in histology is difficult and time-consuming. Mouse embryos that have genetic mutations or that have sustained damage from chemicals are killed, embedded in wax, and sliced into thin sections. Next, they are stained and placed on slides for microscopic examination. “[The new] technique allows us to get at a lot more tissues other than bone, such as internal organs, which [conventional] microCT scans of unstained tissue can’t pick up,” says coauthor Chris Johnson, a distinguished professor of computer science who directs the University of Utah’s Scientific Computing and Imaging Institute.4), a major fixative of choice for electron microscopy, to stain tissues differentially. Images of whole embryos are then made by volumetric X ray microCT, with as little as 2 hours needed to achieve isometric resolutions of 27 μm, or 12 hours to achieve resolutions of 8 μm.The technique uses a 1% solution of osmium tetroxide (OsOThe X ray microCT scans of mouse embryos thus generated are converted using computer visualization techniques into detailed 3-D images that show the mouse’s exterior and interior. Instead of being physically sliced, the special dyes or fixatives permeate the skin and other membranes of a mid-gestation embryo; in older embryos and fetuses, the skin must be removed for the stain to penetrate.Johnson and his group wrote an algorithm that distinguishes and visualizes various organs and structures in the mouse embryo based on the microCT scan data. This produces a virtual rendering of the scan data that also includes a virtual light source. The 3-D embryo image can therefore be rendered with shadows, which makes it easier for the human eye to understand and interpret the image.The new technique furthermore allows users to create transparent images or even produce cutaways, so that internal organs and body parts become visible. Moreover, features as small as 8 μm can be observed. The purpose is to permit geneticists to examine anatomical features of large numbers of embryos, each with a different gene disabled. Then it becomes possible to observe the disruption of normal functions of many genes faster than by existing methods.Indeed, with MBVH, scientists can examine as many as 120 mouse embryos at the same time, each with a different gene knocked out, to detect a specific defect. In addition, they can observe as many sets of 120 embryos as needed in order to detect those that require closer examination at higher resolution—all with the same equipment.4-stained embryos, with a 27-μm isometric resolution, is a vast improvement over the tedious techniques of histological sectioning of early embryos, which needs to be done with painstaking precision and takes 1 to 3 working days to complete.Time is saved, too. The 2 hours it took the research team to obtain scans of OsOMagnetic resonance microscopy has taken some of the procedural sting out of embryo sample preparation, but it still requires expensive, specialized equipment. The team was able to use off-the-shelf specimen scanners, thereby showing that substantial cost savings are possible—a total cost per scan of $1.50 per embryo versus $600.00 per embryo with magnetic resonance microscopy.If higher resolution or increased definition becomes necessary, a stained embryo can be scanned at a resolution greater than 8 μm. Indeed, a 6-μm resolution has been achieved in the same time as the 8-μm scan using a different instrument. Keller and a colleague are now in the process of commercializing the new technique through their company Numira Biosciences.Pax3 gene mutation.For a practical example of how the technique works for high-throughput phenotyping, the researchers used transgenic mouse embryos with substantial malformations of the developing brain and upper spinal cord. Examining these malformations under the dissecting microscope would have been of little use in determining what structure was what. “Even light microscope sections were confusing,” says Keller. The microCT scans were what helped the researchers understand which part of the brain was overgrown and which was underdeveloped as a result of a These embryos were scanned at a resolution of 27 μm, then rendered to visualize the forebrain, midbrain, and hindbrain vesicles; the liver; and the heart wall and cardiac vesicles. The complex 3-D organization of the mutated brain sections was made plainly visible. These views would have been impossible with paraffin-embedded specimen histology, according to Keller and his colleagues.Among plausible applications for MBVH could be enhanced high-throughput analysis of possible side effects of drugs and effects of exposure to environmental contaminants in preclinical toxicology studies. Also feasible might be tumor vascular pattern analysis for biopsies of tumors in patients who undergo anti-angiogenesis therapy. Moreover, the NIH has launched a project to evolve knockout mice for each of the 25,000 mouse genes. Given the large number of samples that can be scanned simultaneously, MBVH technology could help speed up this process.


Before the widespread use of primary percutaneous coronary intervention (PCI) and glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa) left ventricular (LV) thrombus formation had been reported to complicate up to 20% of acute myocardial infarctions (AMI). The incidence of LV thrombus formation with these treatment modalities is not well known.92 consecutive patients with ST-elevation AMI treated with PCI and GP IIb/IIIa inhibitors underwent 2-D echocardiograms, with and without echo contrast agent, within 24–72 hours.Only 4/92 (4.3%) had an LV thrombus, representing a significantly lower incidence than that reported in the pre-PCI era. Use of contrast agents did not improve detection of LV thrombi in our study.The incidence of LV thrombus formation after acute MI, in the current era of rapid reperfusion, is lower than what has been historically reported. A well-recognized complication of acute myocardial infarction (AMI) is the development of a left ventricular (LV) thrombus. Causes of LV thrombus include segmental dysfunction of the infarcted myocardium causing stasis, endocardial tissue inflammation providing a thrombogenic surface, and a hypercoagulable state -6. ThereHistorically, the incidence of LV thrombi complicating AMI had been reported to be 20–40%, and may reach 60% among patients with large anterior wall AMI . Early t®, Bristol-Myers Squibb Inc), with digital storage for later off-line analysis. Second harmonic imaging was used to optimise endocardial visualization. Two level-3 echocardiographers blinded to the clinical details separately reviewed the echo images in each patient. The contrast images were stored and reviewed separately from the non-contrast images. LV thrombus was defined as an echodense mass with definite margins, contiguous but distinct from the endocardium, adjacent to an area of hypo- or akinetic myocardium [Ninety-two consecutive patients presenting to our institution with ST elevation AMI and treated with PCI, rescue angioplasty after failed thrombolysis, or 'facilitated' PCI were enrolled in the study. Written informed consent was obtained from the patients prior to enrolment. Baseline demographic characteristics, pre- and post-intervention Thrombolysis in Myocardial Infarction flow grade, type of intervention, and other therapies instituted were recorded. Two-dimensional echocardiography was performed using a Vivid-7 ultrasound machine  within three days of the PCI, by a registered sonographer, with and without an echo contrast agent  Table . Forty-oFour patients, all with an anterior MI , had a definite LV thrombus, both on unenhanced and enhanced imaging with perflutren lipid microspheres Table . The thrPrevious studies have shown that mural thrombi occur in approximately 20% of all patients who do not receive reperfusion therapy . This inAlthough the introduction of thrombolytic therapy for treatment of AMI improved survival, its impact on the incidence of LV thrombus formation has varied. Bhatnagar, et-al showed a 3-fold reduction in the incidence of LV thrombus in patients receiving early intravenous recombinant tissue plasminogen activator . A sub sCatheter-based reperfusion therapy is superior to thrombolytics in promoting early myocardial recovery, with improved clinical outcomes . PrimaryIt is important to review the role of echocardiography in the diagnosis of LV thrombi. The sensitivity and specificity of 2-D echo in the diagnosis of LV thrombi has been established, even with first and second-generation echo equipment, to be in excess of 92% and 86–88%, respectiviely1. With modern, improved imaging equipment, the sensitivity is expected to be even higher. Nonetheless 2-D echo has certain limitations. First, a small thrombus  may not be accurately detected . Second,The use of contrast agents has been reported to add to the sensitivity of non-contrast 2-D echo  in the dIn conclusion, the incidence of early LV thrombus formation is lower  in this era of primary PCI, coupled with the use of potent antithrombotic and anti-platelet agents, compared to historical data in the pre-PCI era . Routine use of echo contrast agents did not improve detection of LV thrombi in our study.The author(s) declare that they have no competing interests.AR conceived the study and drafted the manuscriptMK recruited patients and assisted in data collectionHR analysed the echocardiographic images and made important revisions to the manuscriptSA participated in acquisition and analysis of the data.AA participated in design and coordination of the study and interpreted the angiogramsJG made important intellectual contributions to the manuscriptGC worked on data analysis and interpretation of echocardiograms, and made important contributions to the manuscript


Inadequate healing of myocardial infarction may contribute to local expansion of the infarct, frequently leading to chamber dilation, heart failure, or myocardial rupture. Experimental evidence in mouse models suggests that Factor XIII might play a key role in wound healing, and low persistent values lead to increased incidence of cardiac rupture following myocardial infarction. Here we would like to share our initial clinical experiences with strikingly similar observations in patients with this grave disease, and compare these observations to experimental findings. Inadequate healing of myocardial infarction may contribute to local expansion of the infarct, frequently leading to chamber dilation, heart failure, or myocardial rupture [1]. Experimental evidence in mouse models suggests that Factor XIII might play a key role in wound healing and low persistent values lead to increased incidence of cardiac rupture following myocardial infarction. For example in heterozygous FXIII deficient mice (characterized by 50% plasma levels of FXIII) 100% die from cardiac rupture following MI  and FXIIWe investigated FXIII levels in three consecutive patients presenting with acute myocardial rupture following myocardial infarction. FXIII levels in these patients were only 57±8% of normal , whereas−/− and FXIII−/+ mice died within 5 days after MI from left ventricular (LV) rupture and had locally reduced levels of FXIII as determined by imaging [2]. In contradistinction, FXIII−/− that received 5 days of FXIII replacement therapy had normal survival rates, although cardiac MRI demonstrated worse LV remodeling in these reconstituted FXIII−/−. Likewise, skin healing was impaired in the same mouse model [3]. In conclusion, the reported clinical experiences and the parallel experimental data support the hypothesis that FXIII deficiency may impair healing in patients with MI while replacement therapy may alleviate complications. A prospective study is warranted to determine the clinical significance of these findings.To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we have recently studied myocardial repair in FXIII deficient mice [2]. All FXIII


We sought to evaluate the impact of different antineoplastic treatment methods on systolic and diastolic myocardial function, and the feasibility estimation of regional deformation parameters with non-Doppler 2D echocardiography in rats.The optimal method for quantitative assessment of global and regional ventricular function in rats and the impact of complex oncological multimodal therapy on left- and right-ventricular function in rats remains unclear.90 rats after subperitoneal implantation of syngenetic colonic carcinoma cells underwent different onclogical treatment methods and were diveded into one control group and five treatment groups (with 15 rats in each group): group 1 = control group (without operation and without medication), group 2 = operation group without additional therapy, group 3 = combination of operation and photodynamic therapy, group 4 = operation in combination with hyperthermic intraoperative peritoneal chemotherapy with mitomycine, and group 5 = operation in combination with hyperthermic intraoperative peritoneal chemotherapy with gemcitabine, group 6 = operation in combination with taurolidin i.p. instillation. Echocardiographic examination with estimation of wall thickness, diameters, left ventricular fractional shortening, ejection fraction, early and late diastolic transmitral and myocardial velocities, radial and circumferential strain were performed 3–4 days after therapy.There was an increase of LVEDD and LVESD in all groups after the follow-up period (P = 0.0037). Other LV dimensions, FS and EF as well as diastolic mitral filling parameters measured by echocardiography were not significantly affected by the different treatments. Values for right ventricular dimensions and function remained unchanged, whereas circumferential 2D strain of the inferior wall was slightly, but significantly reduced under the treatment  without differences between the single treatment groups.It is feasible to assess dimensions, global function, and regional contractility with echocardiography in rats under different oncological therapy. The deformation was decreased under overall treatment without influence by one specific therapy. Therefore, deformation assessment with non-Doppler 2D strain echocardiography is more sensitive than conventional echocardiography for assessing myocardial dysfunction in rats under oncological treatment. Clinical echocardiography has been established as a safe, reproducible, and accurate assessment of cardiac anatomy, hemodynamics, and cardiac function. Commercially available ultrasound imaging systems are capable of resolution approaching that of magnetic resonance imaging as a result of recent computer and transducer technology. Understandably, there is increasing interest in using echocardiography as a basic research tool with standard laboratory animals. Knowledge of baseline normal values in commonly used rat species are limited ,2. PreviAll animal studies were performed in accordance with guidelines for the care and use of laboratory animals at our institutions. 90 male BDIX/HansHsd rats with a body weight between 227 and 312 g were obtained from a single breeding colony . Animals were individually housed and followed free access to standard laboratory food and water ad libitum and 12 hours of light per day. Maintance and care were carried out according to the guidelines of the local Animal Protection Commission. This protocol was approved by our local animal protection committee.5 syngenetic colonic carcinoma cells (DHD/K12/TRb) were implanted subperitoneal in right upper quadrant in male BDIX rats by a median mini-laparotomy under general i.p. anesthesia. After implantation rats were randomized into 6 groups . There were 15 rats in every group. 21 days after tumor implantation all animals of the treatment groups were operated by a standard median laparotomy under general i.p. anesthesia from 6 cm and tumor spread was analysed. After that, we created a surgical tumour debulking with the aim of complete tumour removal in all animals. 4 groups underwent an additional treatment like Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) with mitomycine (15 mg/m2 body surface area) or with gemcitabine (24 mg/kg body weight) , Photodynamic Therapy (PDT) (group 3), taurolidine i.p. instillation (group 4). The rats of one group underwent only surgical debulking (group 5). 21 days after the surgical procedure all animals were sacrified in CO2 chamber and tumor weight, ascites volume and tumor spread, classified by a modified Peritoneal Cancer Index (PCI) were assessed by two independent observers.A new multimodal treatment system in tumor bearing rats was tested. For this purpose 2 × 10The rats were anesthetized with xylazine (3.7 mg/kg i.p.) and ketamine (66.5 mg/kg i.p.), the anaesthesia was maintained throughout the echocardiographic examination, and electrocardiography was continuously monitored from limb leads. Animals were considered sufficiently anesthetized when they became totally unresponsive to a moderate pain stimulus while still normally breathing spontaneously . The anterior chest was shaved and the rats were postioned in left lateral decubitus position during image acquisition.Echocardiographic studies were performed . Images were obtained using a 10S transducer (5.5–12 MHz) with high temporal and spatial resolution. The transducer was placed directly on the chest wall. A complete 2-dimensional, M-mode (according to standards of American Society of Echocardiography), and color and tissue Doppler echocardiogram was performed under anesthesia.Using a zoomed image window, color Doppler myocardial velocity data were acquired at a frame rate of 205–230 frames/s, a sector angle of 30 degrees, and a image depth of 15 mm. Beam focus was set at 10 mm. Digital data of 5 consecutive heart cycles were recorded and transferred to a personal computer workstation for offline analysis.Circumferential 2D strain was calculated from the parasternal short axis view . For radial contractility measurements, strain profiles were analyzed on the inferior and anterior myocardium. Peak systolic strain values were measured in each of 5 heart cycles. The maximal and minimal values were discarded, and the remaining 3 values were averaged. We did not measure strain rate with the speckle tracking method because of the too low temporal resolution and the smoothing of the curves of this method.Systolic 2-dimensional strain , and strain rate (reflects the velocity of strain change) were calculated with the new software for echocardiographic quantification as previously described, based on real-time tracking of natural acoustic marker during two consecutive frames by 2-dimensional strain software. In addition, myocardial velocities with estimation of longitudinal displacement , strain, strain rate, and acceleration during isovolumic contraction were measured in the same segments with conventional TDE .Images and offline reconstructed 2D strain images were compared for each individual rat and interpreted by two investigators, blinded to experimental information and timing of the studies. 2D strain and strain rate were calculated as previously described .The RV morphology was assessed as RV end-diastolic diameter (RVEDD). To assess RV function, the base-to-apex shortening during systole, measured as the tricuspid annular plane systolic excursion (TAPSE) of the lateral portion of the tricuspid annular plane, was recorded in the M-mode format under 2D echocardiographic guidance from the apical 4-chamber view.Radial and longitudinal myocardial strain rate and strain were calculated from color Doppler velocity data using special software  as previously described .For analysis, rats divided into two groups: group A with potential cardiotoxic therapy (group 1 and 2) and group B with non-cardiotoxic therapy (group 3–5).st kind in 3 groups – closed test procedure). Categorical data were tested by means of Fisher's exact test, in particular differences in sensitivity, specificity and accuracy. Proceeding on the assumption that SR measurements are independent from tethering effects of adjunctive segments we choose the segment as statistical unity in the corresponding tests. Simple linear regression, intra-class correlation and Kappa were used for measurement comparisons.Values are expressed as mean ± standard deviation (SD) unless indicated otherwise. Groups were compared by parametric or non-parametric tests . More than 2 groups were analysed using ANOVA  or Kruskal-Wallis test (otherwise). Post-hoc tests were performed  with the help of multiple tests or pair-wise comparisons , whereas it remained unchanged in rats of the treatment group (groups 2–6) 231 ± 17 vs 185 ± 27 bpm; P = 0.62).The hemodynamic effects in normal animals as well as in the different treatment groups are summarized in Table The changes of values for radial and circumferential contraction were summarized in Table In all rats after treatment, the strain profiles demonstrated a postsystolic thickening pattern with circumferential strain in the inferior wall segment, but not in the control group figures +9.Radial strain parameters were not significantly affected by the type of treatment Table . CircumfThis is the first study demonstrating the feasibility of 2D strain echocardiography in rats for noninvasive quantification of regional ventricular function before and after oncological treatment. We could show that conventional systolic and diastolic parameters remained unaffected by the treatment, whereas circumferential 2D strain of the inferior wall was slightly, but significantly reduced after the treatment without differences between the single treatment groups.Previous studies with animal models have examined a wide variety of cardiac diseases and therapies with a trend from invasive to non-invasive hemodynamic assessment in recent years.M-mode and 2D echocardiography are adequate in the absence of regional wall-motion abnormalities. However, the small size of the rat heart and the relatively fast heart rate preclude accurate measurements in case of regional wall-motion abnormalities Previous studies demonstrated that the myocardial velocity gradient derived from Doppler tissue imaging was impaired in rats with pressure overload-induced left ventricular hypertrophy . Strain Cytostatic agents, surgical procedures, and anesthetic agents are known to have effects on myocardial function. Therefore, the choice of anesthetic agent and the potentially cardiotoxic therapy have the potential to affect echocardiographic data directly . MitomycIt was assumed that left-ventricular long-axis function may be more sensitive to ischemia than short-axis function, others could demonstrate that circumferential strain reduction and disorders in twisting are very early signs of myocardial damage in some entities ,11. Serrin vitro and in vivo models, non-Doppler 2D strain echocardiography demonstrated a good correlation and agreement with sonomicrometry values under different contractile conditions [In both nditions ,13. Stranditions . Comparenditions ,14TDI- and non Doppler-2D strain echocardiography permit quantitative assessment of global and regional ventricular function  and coulIn contrast to other studies, we could not see postsystolic thickening or systolic wall thinning, under ischemic conditions .Our findings regarding a possible temporary disturbance of the LV torsion  due to possible afterload mismatch is in accordance to first human findings indicating reduced and delayed diastolic untwisting with aging , and uniIn conclusion, our results demonstrate a high technical reproducibility and diagnostic accuracy with both good spatial and temporal resolution of conventional 2D-, TDI- and Non-Doppler 2D strain echocardiography.We conclude that the demonstrated negative effect on circumferential strain of the inferior wall was a general effect of the sedation plus oncological therapy and not induced by one special modality of therapy. Deformation assessment with non-Doppler 2D strain echocardiography is more sensitive than conventional echocardiography for assessing myocardial dysfunction in rats under oncological treatment.in vivo protocols in small animals.Non-Doppler 2D strain echocardiography represents a new, powerful method for the evaluation and quantification of global and regional myocardial function for experimental The methods used in this study were not compared to a gold standard technique  as these methods were not part of the protocol.The heart rate in the animals was greater than 300/min, even under anesthetic conditions. The frame rate had to be set between 180 and 210 for tissue Doppler measurements and between 60 and 80 for non-Doppler 2D strain calculations, in order to balance the requirements for temporal and spatial resolution.Deformation measurement is limited in the short axis views due to twisting and swinging in the azimuthal plane of the heart and the movement by respiration. We preferred these views for deformation calculation because of the difficulty in acquiring good apical images as previously described .Histological examinations and follow-up examinations were not performed. We can only speculate about the temporary character of the changes of circumferential strain values in the treatment group.LV = left ventricularECG = electrocardiogrampw- Doppler = pulsed wave DopplerLVEF = left ventricular ejection fraction2D = two-dimensionalTDI = tissue Doppler imagingSR = strain rateROI = region of interestThe author(s) declare that they have no competing interests.JH, FK and ACB have designed and performed the study and have written the manuscript. JH and FK have equally contributed to this study. JH, FK, ACB SE, MB, AG, AP, GB have performed echocardiographic measurements and participated in the study design and coordination. JH, CJ and JM have performed the oncological and surgical therapy. KW has supported the statistical analysis of the study. All authors have read and approved the final manuscript.


Left sided superior vena cava (SVC) is an uncommon anomaly noted in the general population. It adds complexity to the procedure, when attempting to place pacing or defibrillator devices into the heart. Here we report a case where the leads were placed through the left sided SVC into the right sided chambers giving an interesting X-ray appearance. Seventy two year old female with dilated cardiomyopathy and left bundle branch block, was referred for cardiac resynchronization therapy. She previously had single chamber defibrillator and had developed worsening heart failure over the years. Under fluoroscopy, her  defibrillator lead was noted to be entering the heart from the left side. With contrast injection from left antecubital vein, she was found to have persistent left superior vena cava ( SVC) and absent innominate vein. Dye flow was extremely rapid from left SVC through coronary sinus (CS), that it was difficult to visualize the branches of coronary sinus. When contrast was administered in the coronary sinus, after occluding SVC and CS os, no significant branches were noted to be present. Therefore LV lead could not be placed by endocardial approach. However atrial lead was placed through the CS into the right atrium, giving this unusual but interesting appearance of the chest X-Ray. ,Figure 2The incidence of Left SVC is about 0.3% of the general population as evident  from autopsy studies, and about 0.47% of  patients receiving pacemaker and defibrillator devices . In a ca


Echocardiography plays an integral role in the detection of mechanical dyssynchrony in patients with congestive heart failure and in predicting beneficial response to cardiac resynchronization treatment. In patients who derive sup-optimal benefit from biventricular pacing, optimization of atrioventricular delay post cardiac resynchronization treatment has been shown to improve cardiac output. Some recent reports suggest that sequential ventricular pacing may further improve cardiac output. The mechanism whereby sequential ventricular pacing improves cardiac output is likely improved inter and possibly intraventricular synchrony, however these speculations have not been confirmed. In this report we describe the beneficial effect of sequential V-V pacing on inter and intraventricular synchrony, cardiac output and mitral regurgitation severity as the mechanisms whereby sequential biventricular pacing improves cardiac output and functional class in 8 patients who had derived no benefit or had deteriorated after CRT. Online tissue Doppler imaging including tissue velocity imaging, tissue synchronization imaging and strain and strain rate imaging were used in addition to conventional pulsed wave and color Doppler during sequential biventricular pacemaker programming. Tissue Doppler imaging (TDI) has been shown to play a pivotal role in the detection of mechanical asynchrony in patients with congestive heart failure (CHF) and to predict improvement functional class and cardiac function in response to cardiac resynchronization treatment (CRT) -5. BivenMitral inflow and LV outflow PW Doppler data as well as TDI were performed using GE Vivid 7, Vingmed ultrasound system using conventional methods and analyzed online using custom built "Q analysis" software. For both PW and TDI, data was averaged from 5 cardiac cycles for each AV and VV delay. Optimal AV delay was determined first using Ritter's , and iteBaseline characteristics of the study population along with echocardiographic findings are shown in table Recurrent class III heart failure symptoms occurred in an 87 yr old patient 45 days after a favorable response to CRT . BNP was 2020 pg/ml compared to 1885 pg/ml pre CRT. Significant lateral and posterior wall delay was seen on TSI. Progressive increase in LV pre-excitation from 4–50 ms under TSI guidance led to a decrease and finally abolition of posterolateral wall delay and improvement in LV velocity times integral (VTI) at LV pre-excitation of 50 ms  of 20% and marked mechanical dyssynchrony on TDI. Following implantation of biv device an optimization of pacemaker was requested. There was sinus rhythm, moderate mitral regurgitation (MR), moderate to severe tricuspid regurgitation and peak pulmonary artery pressure (PAP) was 65 mmHg. Using Ritter's and iterative method, optimal AV delay was determined to be 100 ms. By TSI least dyssynchrony appeared to be present at an LV pre excitation of 20 ms Figure  and MR wA 67-year-old Caucasian male underwent aortic valve replacement with a bioprosthetic valve, mitral valve annuloplasty and epicardial LV pacing for CHF, complete heart block, LVEF of 12%, NYHA class III symptoms and BNP of 1442 pg/ml. NYHA improved to class II, 2 months later and he was referred for biv pacemaker optimization. LVEF was 38%, there was a normally functioning bioprosthetic aortic valve, a mitral annuloplasty ring with trivial MR and pulmonary artery pressure was 35 mmHg. There was in sinus rhythm and the baseline pacemaker settings were A-sensed AV delay of 180 ms and LV pre excitation of 5 ms with biv pacing. Optimal AV delay by iterative method was 180 ms. LV pre excitation of 10 ms abolished the marked delay seen on TSI in the entire lateral and posterior as well as in the basal inferior wall . Pacemaker was programmed at sensed AVD of 100 ms and LV pre-excitation of 20 ms. No E and A separation was seen at an AVD of 100 ms. Marked delay in the right ventricular free wall and interventricular septum decreased progressively as the VV settings were changed to VV 0, right ventricular pre-excitation of 10 and then 15 ms Figure . FurtherAn 85 year old female underwent CRT for ischemic dilated cardiomyopathy, LVEF of 30%, left bundle branch block and NHYA class III symptoms and presence of marked mechanical dyssynchrony. LV lead was in the lateral coronary sinus branch. She was referred for optimization due to no improvement in symptoms 2 months post CRT. Pacemaker was programmed at an A sensed AVD 110 ms and LV pre-excitation of 20 ms. Native AV delay was 110 ms. LVEF was 35% and there was trace MR. Right ventricular pre-excitation caused improvement in LV velocities, strain and strain rate Figure , C and FA 75 year old female with known mitral valve prolapse and severe MR for 7 years presented 10 months post CRT. After initial response to CRT, worsening shortness of breath and NYHA class III symptoms developed 2 months prior to presentation. Sensed AVD was 180 ms and LV was pre-excited by 20 ms. There was severe eccentric anterior MR jet originating from a prolapsed middle scallop of posterior leaflet Figure . There wWe describe the benefit of individualized AV and VV programming in symptomatic patients post CRT using TDI and conventional echocardiographic parameters. We found that sequential ventricular pacing led to improvement in cardiac output by improvement of intra and interventricular synchrony, strain and/or by reduction MR in our patients who had continued to be symptomatic post CRT. In an earlier report we have described benefits and mechanisms of benefit of AV delay optimization using echocardiography in symptomatic patients post CRT . Our finAlthough conventional simultaneous CRT improves LV performance compared with native rhythm, LV hemodynamics can be further improved by individually programming the VV interval to the optimal pacing mode in at least 80% of patients ,18. VV oAs such both AV and VV optimization should be performed in patients whose device allows these programming features. Most patients require upto 20 ms of LV pre-excitation and few patients benefit for upto 40 ms of LV pre-excitation. ,19 One sMultiple invasive and noninvasive methods have been attempted to identify the best AV delay for CRT, but all suffer from a combination of high patient risk, cost, complexity, and low reproducibility. These methods include invasive measurement of LV dp/dt ,22, invaInstead of myocardial displacement displayed by color codes as has been described for sequential biv programming earlier  we used We also used myocardial strain and strain rate that depict myocardial deformation and rate of myocardial deformation in color . Online We found that each patient required individual assessment using TSI, strain and velocity and strain rate maps. Although in general findings in one TDI modality agreed with findings from another TDI modality, these did not always concur. We also found that presence of delayed contraction as shown in Figure Ours is not a consecutive series of patients, rather a collection of patients in whom TDI and color Doppler evaluation during VV optimization allowed novel observations that provide insight into the mechanism of failure of CRT in heart failure. Our report therefore does not allow insight into the prevalence of mechanisms described in this report that lead to lack of beneficial effect from CRT.VV optimization guided by assessment of intra and interventricular synchrony by TDI can lead to improvement in inter and intra ventricular synchrony, function, and cardiac output in patients who have not responded to CRT.AV = AntrioventricularBiv = BiventricularCHF = Congestive Heart FailureCRT = Cardiac Resynchronization TreatmentEF = Ejection FractionLV = Left VentricularMR = Mitral RegurgitationNYHA = New York Heart AssociationPAP = Pulmonary Artery PressureTDI = Tissue Doppler ImagingTSI = Tissue Synchronization ImagingVTI = Velocity Times IntegralThe author(s) declare that they have no competing interests.TZN conceived and designed the study, performed all optimization procedures and drafted and critically revised the manuscript. AMR participated in the design of the study and performed the data and statistical analysis. CTP participated in the design of the study and drafting of the manuscript. All authors read and approved the final manuscript.