Objective: Esophageal stethoscope has the advantage of being non-invasive, easily placed and capability to monitor the heart sound. This study was designed to determine whether the ratio of S1 to S2 analyzed by esophageal stethoscope and wireless bluetooth transmission can be accurate indicator that express the correlation with blood pressure.Methods: Total 33 adult male and female without cardiac disorder and with normal heart rhythm were selected randomly as the subjects of this Study. Two microphones were used with one for acquisition of heart sound by connecting it to the esophageal stethoscope while the other was used to measure the background noise in the operating room. After having transmitted the heart sound measured with the esophageal stethoscope to the receiver by using bluetooth module, it was saved in PC and outputted, following removal of noise in the operating room and the respiratory sound. S1 and S2 were measured with computation of the ratio of S1 to S2. Correlations between the systolic blood pressure with each of the S1, S2 and ratio of S1 to S2 were examined by using correlation analysis.Results: The ratio of S1 to S2 displayed the highest correlation with the systolic blood pressure, with S1 and S2 also displaying positive correlation with the systolic blood pressure.Conclusion: As the result of analysis of the heart sound and the systolic blood pressure measured by using the esophageal stethoscope, the radio of S1 to S2 displayed greater correlation with the systolic blood pressure in comparison to the S1. Among these monitoring methods, the esophageal stethoscope has the advantage of being non-invasive, ease of placement, and being able to measure not only the heart sound but also to monitor the temperature and the respiratory sound of the patients. The measurement of heart sound through the esophageal stethoscope is more useful in measuring the changes in the heart sound consistently in accordance with time in comparison to the precordial stethoscope since it is fixed at one location throughout the surgery. In the case of a specially designed stethoscope, ECG through esophagus can be recorded, which can be useful in diagnosis of atrial arrhythmia and right or left ventricular posterior wall ischemia. In addition, the esophageal stethoscope is effective in the treatment of sinus bradycardia or atrio-ventricular rhythm.2 were carried out, there are not many researches that analyzed the heart sound and on its relationship with the hemodynamic indices using the esophageal stethoscope. Accordingly, this study aims to analyze the heart sound by using the esophageal stethoscope and the wireless bluetooth transmission, and to examine whether the ratio of S1 to S2 can be used as objective index with correlation with the blood pressure.Although numerous researches that reported correlations between hemodynamic indices such as the ejection fraction and the ratio of S1 to S2 in previous researches using the precordial stethoscopeThirty three (33) adult male and female without cardiac disorder and with normal heart rhythm who corresponded to the physical class classification I or II of the American Society of Anesthesia (ASA) among the patients for whom general anesthesia was planned were selected randomly as the subjects of this study . This st®, Fresenius Vial, France). The radial artery was secured for continuous measurement of the blood pressure and the esophageal stethoscope was positioned to listen to heart sound. The esophageal stethoscope was positioned at the depth of 28-32 cm from upper incisor where the S1 sound was heard the loudest, the location reported to be the best position to listen to heart sound3, and the omnidirectional microphone with frequency response range of 20-20,000 Hz  was connected.All the patients arrived at the operating room without undergoing premedication, and total intravenous anesthesia was induced with propofol and remifentanil by using the target controlled infusor  for application in 8-bit control was used as micro-controller, while AD822  was used as the amplifier and FB570  as the bluethooth module. Receiver plays the role of storing in the PC and outputting the heart sound data transmitted from the transmitter after having received and signal processed the data. Portion of the recorded data through the esophageal stethoscope that coincided with the noise in the operating room was removed and filtering was performed by using Cool Edit Pro 2.1 and noise such as respiratory sound, etc was removed with low-pass filtering.Since the intensity of heart sound can differ according to breathing, comparison was made consistently with the end-tidal blood pressure. S1 and S2 were measured at 5 minutes after induction of anesthesia. They were measured as the mean value of data for 3 seconds, data with the radio of S1 to S2 computed separately. The sound pressure was indicated with the sound pressure level (SPL) and expressed with the unit of sound milli pressure level (SMPL). Correlation with each of S1, S2 and the radio of S1 to S2 was analyzed on the basis of the systolic arterial blood pressure. SPSS  was used for statistical analysis. Pearson correlation was used for analysis of correlation between the blood pressure and each of the heart sounds, and it was determined to be statistically significant if P value is less than 0.05. The heart sound measured through esophageal stethoscope was stored in the receiver through the wireless Bluetooth transmission, and S1 and S2 were easily distinguished by removing the external noise through the computer recording program and filtering . As the 4 and phonocardiography5 have been studied in various researches. Vibration associated with sudden acceleration or deceleration of blood in the cardiovascular system is the key compositional element of the heart sound.6 This is divided largely into the 1st heart sound (S1) generated at the time of the closure of the mitral valve and the tricuspid valve, and the 2nd heart sound (S2) generated at the time of closure of the aortic valve and the pulmonary valve. S1 is a slightly low-pitch sound that is heard the loudest at the apical region as the result of the closure of atrioventricular valve, while S2 is a slightly high-pitch sound heard at the apical region as the result of the closure of arterial valve.7Chest auscultation8 S1 increases in the event of shortening of the diastolic phase due to tachycardia, increase in blood flow from atrium to ventricle due to increase in the cardiac output, increase in blood flow from atrium to ventricle due to the mitral valve stricture, and contraction of ventricle with abnormally short interval following the contraction of atrium similar to shortening of the PR interval.6S1 is composed of M1 that is generated with the closure of mitral valve and T1 generated with the closure of tricuspid valve, and there is hypothesis that it is related to the movement of blood.9-11The mitral valve closes when the left ventricular pressure exceeds the left atrial pressure in the heart cycle, and, since the blood flows from high to low pressure, the mitral valve closes in order to prevent counter flow of blood from the left ventricle to the left atrium as the left ventricular pressure becomes larger. Greater and quicker the increase in the left ventricular pressure, more powerful the closure of mitral valve, thereby increasing the intensity of S1. Therefore, on the basis of this fact, it is possible to presume that S1 is related to the myocardial contractile force. In fact, there is a report that S1 reflects the myocardial contractile force as the result of simultaneous monitoring of echocardiography, Doppler flow and phonocardiogram.12 as well as report that amplitudes of S1 and S2 decrease following induction of inhalation anesthetics.13 S2 is divided into A2 arising from the closure of aortic valve and P2 due to the closure of pulmonary valve, and the intensity of S2 increases with greater intensity in the closure of aortic valve. The aortic valve closes in order to prevent counter flow of blood, which was infused into the aorta from the left ventricle, into the left ventricle again.In addition, there is a report in a research using experimental dog that when the systolic left ventricular pressure is increased through injection of inotropics, S1 increases in proportion14The closure of aortic valve is caused by the difference in the aortic pressure and the left ventricular pressure, and the intensity of its closure increases with the increase in the difference in these pressures. Such pressure difference is determined mainly by the internal pressure of the aorta because the left ventricular pressure at diastolic phase under the normal situation is close to zero. Resultantly, the internal pressure of the aorta is the force that closes the aortic valve. If situation in which increase in the flux of blood from the left ventricle to the aorta occurs, the aorta is further expanded and the internal pressure of the aorta increases in proportion, thereby resulting in the increase in the intensity of closure of the aortic valve with ensuing increase in the intensity of S2. There also is a report that intensity of S2 decreases in patients with reduction in the ejection fraction in comparison to normal person.6 The time of the closure of aortic valve is not affected significantly by breathing. Since the lung plays the role of buffering the changes in the blood flow, blood that flows into the left ventricle through the left atrium from the lung is maintained almost consistently throughout the breathing cycle. In addition, paradoxical splitting in which P2 occurs prior to A2 may occur. The most common reason for this phenomenon is the delay in the excitement of the left ventricle due to left bundle branch block and right ventricular extra-heartbeat.6,15 In this Study, A2 and P2 would not have been clearly distinguished since the blood pressure and the heart sound was measured at the end of the exhalation phase simultaneously.Under normal situation, S2 is clearly divided into A2 and P2 because of the delay in the closure of pulmonary valve with increase in the stroke volume and the time with increase in the flux of blood into the right ventricle at the time of diastolic phase.16,17 In addition, the intensity of S1 decreases if the increase in the left ventricular pressure heart beat is slow, if the PR interval is long and if the valve is closed incompletely due to the reduction in the valve tissue as in the case of mitral valve closure deficiency.6,15In this Study, those with cardiac disorders and irregular rhythm were excluded because such could affect the intensity of S1. Since the diastolic phase volume changes if the interval of the heart beat is irregular as in the case of atrial defibrillation, the intensity of S1 can change at every interval due to changes in the contractile force of the left ventricle at every heartbeat. In the case of complete AV block, S1 with enormous sound (cannon sound) can occur with the contraction of both the atrium and the ventricle occurring completely simultaneously at times.2 There also is a report that S1/S2 is reduced with reduction in contractile force as the result of analysis of the heart sound while performing percutaneous coronary intervention.18 It is possible to establish hypothesis that S1/S2 is related to the myocardial contractile force and correlated to the blood pressure on the basis of these results. While all of S1, S2 and S1/S2 were correlated with the blood pressure, S1/S2 displayed the highest correlation. This signifies that the changes in S1 is greater than the changes in S2 in accordance with the changes in the blood pressure, and it is deemed to be the result of S1 better reflecting the myocardial contractile force than S2. In addition, based on the results, S1/S2 is determined to be more appropriate as an index to indicate the hemodynamic changes in comparison to S1.Although there is not much research result on the relationship between the ratio of S1 to S2 (S1/S2) and the hemodynamic indices, there is a report that S1/S2 is reduced with lowering of the ejection fraction and lowers the changes in the ventricular pressure (dP/dt) for each unit time in research that used echocardiography, catheter and phonocardiogram.19 demonstrated that the intraoperative esophageal stethoscope provides a remarkably effective technique for monitoring and evaluating patent ductus arteriosus (PDA) ligation. Kahrom M et al20 used esophageal stethoscope to research cardiac murmurs in PDA. Although the precordial stethoscope can be used to analyze the heart sound, analysis is difficult and complicated due to noises and overlapping of sound. Accordingly, this experiment used the esophageal stethoscope. Noise in the operating room was measured separately and removed using program, and breathing noise could be removed by executing simple low-pass filtering. Although the left ventricular function could be assessed, and counter-flow of valve, stricture, area and pressure difference and the contractile force of ventricle could be measured accurately by using the echocadiography and Doppler for the purpose of the monitoring of the surgery patients,21 these equipment are expensive with specialized and complex process of installation and analysis.Esophageal stethoscope and heart sounds have been studied in various clinical studies. Nezafati MH et alTherefore, it would be possible to more easily analyze the heart sound and monitor the hemodynamic changes of the patients by using the esophageal stethoscope and the wireless Bluetooth transmission for which installation and analysis is relatively simple if additional researches on the relationship between the hemodynamic changes and the heart sound are carried out in the future.As the result of analysis of the heart sound and the systolic blood pressure through the esophageal stethoscope and the wireless Bluetooth transmission, it was possible to confirm that the blood pressure has positive correlation with each of S1, S2 and S1/S2. Since S1/S2 displayed the highest correlation among these, it could be used as an appropriate index to display the correlation with the blood pressure. In addition, development of equipment for the monitoring of the hemodynamic changes of patients by using the esophageal stethoscope and the wireless Bluetooth transmission, for which installation and analysis is simple, could be expected through additional researches. KHL & YDS: Conceived, Designed and did statistical analysis & editing of manuscript.SHP, JHB, HJL, SJK, JYS & YJC: Did data collection and manuscript writing.YDS: Did review and final approval of manuscript.


Elevated pulmonary vascular resistance occurs during the first days after birth in all newborn infants and persists in infants at risk for bronchopulmonary dysplasia (BPD).It is difficult to measure in a non-invasive fashion. We assessed the usefulness of the right ventricular index of myocardial performance (RIMP) to estimate pulmonary vascular resistance in very low birth weight infants.Prospective echocardiography on day of life (DOL) 2, 7, 14, and 28 in 121 preterm infants  and did not develop BPD . RIMP declined steadily in non-BPD infants but not in BPD infants .In preterm infants, a decline in RIMP after birth was not observed in those with incipient BPD. The pattern of RIMP measured in preterm infants is commensurate with that of pulmonary vascular resistance. Bronchopulmonary dysplasia (BPD) remains the most common long-term complication of very preterm birth An easily measured Doppler index  infants with BPD compared to infants without BPD.A prospective study was conducted at a single tertiary care perinatal center from September 2008 to January 2010. For this study we enrolled 121 of the 168 admitted preterm infants born at our hospital and below <32 weeks gestational age and birth weight <1500 g . 36 infaInfants who had a congenital heart malformation or infants who died within 48 h of birth or infants who died within the first month of life and therefore did not undergo the full set of four sequential echocardiograms were excluded.All infants received standard intensive care and no infant required sedation or muscle relaxation for mechanical ventilation. The study protocol was approved by the local institutional review board , and written informed parental consent was obtained.All patients were examined using a 3.9 to 6.9 MHz transducer interfaced with a Vingmed System Vivid 7 Dimension'06 . Transthoracic imaging was performed on the neonates at ages 2, 7, 14 and 28 days in a supine position without sedation.The presence or absence of a patent ductus arteriosus (PDA) was determined by direct ductal imaging in the high left parasternal view with colour Doppler mapping. Doppler measurements of the RIMP were performed using the method proposed by Tei et al Patient characteristics were described by rates (%) or median values and quartiles and compared using Fisher's exact test or the Mann-Whitney U-Test as appropriate. The echocardiographic parameters a and b were measured of three consecutive cardiac cycles. The calculated means were used to determine RIMP and the coefficient of variation was used to describe the intra-observer variability presented by median and quartiles. Offline analysis of the data was performed using a special software program . All measurements were performed by a single, non-blinded investigator (S.R.), precluding any inter-observer variability. The RIMP of the patient groups was described by median and quartiles and compared using the Mann-Whitney U-Test. Spearman rank order correlation coefficients were calculated to investigate the impact of clinical and hemodynamic parameters on RIMP at the 4 measurement time points. The Friedman Test was used to investigate the age dependency of RIMP. Statistical analysis was performed using SPSS . A p value of <0.05 was considered statistically significant.We were unable to assess the RIMP successfully by Doppler at all measurement time points because of an unclear waveform depicting the right ventricular inflow or outflow. The assessment success rates at day of life (DOL) 2, 7, 14 and 28 were 78%, 73%, 67% and 79%, but there were no statistically significant differences in the drop out frequency between the patient groups at the four time points. The intra-observer variability of the both measurement parameters a and b was comparable with a median (quartiles) coefficient of variation of 3.4% (2.0%–5.1%) for a and 4.2% (2.7%–6.4%) for b.RIMP was strongly age dependent (p<0.001) and decreased continuously during the neonatal period. The decrease in RIMP during the first two weeks of life differed significantly between non-BPD infants and those infants who developed a BPD as shown in The course of RIMP was age-dependent and differed between infants with and without BPD. Therefore the effect of PDA and mechanical ventilation was investigated in the subgroups with or without BPD. At DOL 2 all BPD infants had a PDA, so its impact on RIMP could not be investigated. In both patient groups defined by the presence or absence of BPD, there was no statistically significant effect of PDA on RIMP at DOL 7, 14, and 28 . At DOL Our data confirm the hypothesis that RIMP differs between VLBW infants without BPD and infants who develop BPD between 7 and 28 days of life. RIMP values were significantly higher on DOL 7, 14 and 28 in infants with a subsequent diagnosis of BPD compared to controls.Our results reveal that average RIMP values in VLBW infants are relatively high at DOL 2 but fall rapidly during the neonatal period in preterm VLBW infants similar to the drop observed in term and near-term infants and confirmed the longitudinal time course of RIMP during the neonatal period as already demonstrated by Murase et al. These time course changes in RIMP reflect a differential decline of pulmonary vascular resistance in infants with a BPD diagnosis. VLBW infants who developed a BPD showed only a slight decrease in RIMP during the first month of life compared to infants without BPD.It is known that several cardiovascular changes take place during the early neonatal period that involve the adaptation of myocardial performance, such as the closure of fetal shunts, increased pulmonary circulation, and increased peripheral systemic circulatory resistance. VLBW infants in particular are at higher risk of hemodynamic instability in postnatal cardiovascular adaptation and for developing BPD Especially shortly after birth, PVR and pulmonary arterial pressure fall rapidly, whereas pulmonary blood flow reaches systemic levels. The exact mechanisms by which these dramatic changes in PVR occur with the onset of ventilation at birth have been investigated extensively The observation that RIMP represents global RV function was already reported by Sugiura et al. from recent animal studies. Global RV function is always regulated by both myocardial performance and pulmonary artery pressure as RV afterloads Several authors reported that RIMP is readily available in tachycardia, independent of heart rate or blood pressure, and not affected by tricuspid regurgitation In contrast, the most widely used echocardiographic parameter, the “E/A ratio”, for evaluating RV diastolic function in adults Despite the fact that current therapy during the neonatal period includes surfactant replacement, supportive ventilation strategies with lower mean airway pressures and permissive hypercapnia, inhaled and systemic corticosteroid therapy, bronchodilators, diuretic therapy, vitamin A therapy, and optimal nutrition, BPD remains a major cause of morbidity and mortality among VLBW infants. At the moment, there is no “magic” biomarker for the early identification of infants who subsequently develop BPD A limitation of our study is that the interval between the end and onset of tricuspid inflow and the ejection time are measured sequentially and not during the same cardiac cycle. Future investigations might compare RIMP obtained by conventional pulsed Doppler echocardiography with data derived from tissue Doppler echocardiography, which allows for the simultaneously measurement of both the diastolic and systolic intervals from the myocardium, or other methods to assess systolic and diastolic ventricular function. However, previous studies have already shown a relatively good correlation of RIMP obtained by pulsed Doppler and tissue Doppler echocardiography In conclusion RIMP, which combines systolic and diastolic time intervals, is a feasible approach for assessing global RV function in VLBW infants. We have shown that RIMP values were significantly higher in infants with a subsequent diagnosis of BPD compared to controls indicating an increased pulmonary vascular resistance. Using RIMP as a sole marker of global RV function is currently not recommended by the American Society of Echocardiography


Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder of elderly people. Cardiac dysfunction is a marker of grim prognosis in MDS. We evaluated cardiac dysfunction of MDS patients with or without transfusion dependency by tissue doppler echocardiography. We found the average values of ventricular end-systolic and end-diastolic volumes in transfusion dependency MDS group higher than others. These results were strongly correlated to hemoglobin levels. Tissue Doppler Echocardiography should be routinely performed in MDS patients to detect preclinical cardiac alterations and prevent more heart insults in this group of chronic anemic aged patients. Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder and anemia with transfusion dependency is detected in up to 60% of patients . Early rWe evaluated three groups of MDS patients: cases with transfusion dependency (T-MDS), patients without transfusion dependency (NT-MDS) and age-matched controls. Transfusion dependency was considered as reported by Malcovati et al. . Echo-DoParametric data were analyzed by “one-way” analyzes of variance (ANOVA) with Bonferroni’s Multiple Comparison as a post-test. Non-parametric data were analyzed by Kruskal-Wallis. The studies of correlation was assessed by Pearson’s correlation coefficient (r).2, 26.6 ± 5,2 mL/m2, 22.8 ± 8 mL/m2 respectively) (p <0.004.). A strong correlation between hemoglobin levels and LVEDV (left ventricular end-diastolic volume), LVESV (left ventricular end-systolic volume), LAV  and LAV index was observed, with r values of −0.4, -0.4, -0.53 and 0.51 respectively . See Figure 1. Otherwise, we found no correlation between ferritin levels and echocardiographic parameters.The three groups were composed of 13 T-MDS, 21 NT-MDS and 14 controls. There were no significant differences between groups. See Table The reduction of blood viscosity in severe anemia increases blood return  and ventThe T-MDS group showed no clinical sign of cardiac dysfunction. Otherwise, cardiac alterations were detected by tissue-doppler echocardiography, a relative fast and cheap bedside method to evaluate heart function. Echocardiography should be routinely performed in MDS patients to detect preclinical cardiac alterations and prevent more heart insults in these group of chronic anemic aged patients.NT-MDS, Non-transfused patients; T-MDS, Transfused patients; LVDD, Left ventricular diastolic diameter; LVSD, Left ventricular systolic diameter; IVS, Inter-ventricular septum; LVPW, Left ventricular posterior wall; LVEDV, Left ventricular end-diastolic volume; LVESV, Left ventricular end-systolic volume; LAV, Left atrial volume; RCC, Red cell concentrate; VD, Ventricular dysfunction.The authors declare that they have no competing interests.CCMC was the principal investigator and takes primary responsibility for the paper. CBGG provide technical support. MRAM participated in the statistical analysis. JCS performed the laboratory work for this study and edited the manuscript. SMMM provided critical revision. RFP coordinated the research and wrote the paper.


The very unusual case of a 35-year-old obese male patient with a left ventricular (LV) thrombus secondary to a silent myocardial infarction and resultant shower emboli to multiple arterial sites is described. His presentation with acute limb ischemia led to arterial imaging and the identification of the underlying cardiac pathology in addition to splenic and bilateral renal infarcts. He was also found to suffer from previously undiagnosed hypertension. He underwent femoral embolectomy and multiple arterial revascularization attempts but required bilateral above knee amputations and a prolonged intensive care unit stay. This rare and extreme example of a LV thrombus in a young male emphasizes the potential sequellae of the condition. Furthermore, with the increasing incidence of obesity this case demonstrates the importance of considering undiagnosed cardiovascular risk factors when assessing obese patients. The very unusual case of multiple arterial emboli from a left ventricular (LV) thrombus following a silent myocardial infarction (MI) in a 35 year old obese male is presented. Such a severe example reminds health professionals of the potential sequellae of this recognized complication of MI and to bA 35-year-old obese (BMI>40) male was transferred to the emergency department (ED) at our institution critically unwell with an acutely ischemic right lower limb. He was tachypnoeic, tachycardic and had a Glasgow Coma Score of 11 with oxygen saturations of 78% on air. On examination his right lower limb was cold and pulseless. Arterial blood-gas sampling revealed a metabolic acidosis . A collateral history from his family revealed he was an ex-smoker and apart from obesity did not have any known cardiac risk factors. However, he had been experiencing bilateral loin pain for the previous 3 days and had been receiving antibiotics for a presumed pyelonephritis.An ultrasound performed in the ED showed a left ventricular (LV) thrombus on pericardial windows. Following stabilization and intubation, computed tomography angiography (CTA) showed occluded right external and left internal iliac arteries, an acute splenic infarct, bilateral renal infarcts and a significant filling defect in the left ventricle Figures  and 2. IEchocardiography demonstrated severe LV dysfunction (LV ejection fraction of 15%) and dilatation (LV diameter of 7 cm in systole) with an extensive 4 cm thrombus within the LV . TroponiAt 1-year follow-up he is doing well. His cardiac function has dramatically improved  with only mildly impaired LV function and complete resolution of the LV thrombus.The case described provides a very rare example of the complications from a LV thrombus in such a young patient. In addition to LV aneurysm and dilated cardiomyopathy, LV thrombus can complicate MI, where akinesis promotes blood stasis and thrombus formation. EmbolizaIt is likely that the splenic and renal infarcts identified on CTA were responsible for the preceding symptom of loin pain. Renal infarction presents with loin pain and microsopic hematuria and has been reported secondary to LV thrombus. The mimicking of ureteric colic demonstrates the diagnostic difficulties associated with this condition and may Obese patients can have undiagnosed cardiovascular risk factors and as such may present atypically with cardiovascular disease. In this The causes for MI in young patients differ to the primarily atherosclerotic etiology seen in older patients. These include hypercoagulable states, spontaneous coronary artery dissection, congenital coronary artery abnormalities, accelerated atherosclerosis and coronary artery spasm. The exacLV thrombus can embolize to multiple arterial sites with severe results. Obese patients may have hidden cardiac risk factors and physicians need to be alert to atypical presentation of cardiovascular disease in this patient group.Informed verbal and signed consent was given by the patient in this case.


Early detection of heart failure is essential to effectively reduce related mortality. The quantification of the mechanical properties of the myocardium, a primordial indicator of the viability of the cardiac tissue, is a key element in patient’s care. Despite an incremental utilization of multi-parametric magnetic resonance imaging (MRI) for cardiac tissue characteristics and function, the link between multi-parametric MRI and the mechanical properties of the heart has not been established. We sought to determine the parametric relationship between the myocardial mechanical properties and the MR parameters. The specific aim was to develop a reproducible evaluative quantitative tool of the mechanical properties of cardiac tissue using multi-parametric MRI associated to principal component analysis.Samples from porcine hearts were submitted to a multi-parametric MRI acquisition followed by a uniaxial tensile test. Multi linear regressions were performed between dependent (Young’s modulus E) and independent  variables. A principal component analysis was used to convert the set of possibly correlated variables into a set of linearly uncorrelated variables.-2, and 5.85±0.21 mm2/s for ADCx10-4 were measured. Multi linear regressions showed that only 45% of E can be explained by the MRI parameters. The principal component analysis reduced our seven variables to two principal components with a cumulative variability of 63%, which increased to 80% when considering the third principal component.Values of 46.1±12.7 MPa for E, 729±21 ms for T1, 61±6 ms for T2, 26±7 for T2*, 35±5% for MTRx100, 33.8±4.7 for FAx10in vitro porcine model. Our in vitro experiments will now allow us focused in vivo testing on healthy and infracted hearts in order to determine useful quantitative MR-based biomarkers.The proposed multi-parametric MRI protocol associated to principal component analysis is a promising tool for the evaluation of mechanical properties within the left ventricle in the  Heart failure is a progressive disease in which the damage to the cardiac tissue can be of primary or secondary origin. It entails incapacity of the myocardium to sustain an adequate blood flow for the systemic needs of the organism. It is a major health problem approaching epidemical proportions in industrialized countries and imputing billions of dollars in the healthcare resources. It is estimated that at least one third of adults over 55 years old will develop heart failure later in life. The ultimate risk of heart failure is accrued death, with a survival rate of 35% five years after diagnosis. EchocarThe mechanical properties of the myocardium are a primordial indicator of the viability of the cardiac tissue and heart failure. Uniaxial, biaxial and equibiaxial stretching tests were performed on excised ventricular samples. However, translating knowledge from freshly euthanized animals to live functioning hearts with reliable measures of the mechanical properties of the myocardium remains difficult because of the vascularity of the tissue that changes drastically immediately after death. Moreover, these mechanical properties vary according to the experimental loading protocol and the mathematical model. To solve the finite elasticity stress estimation problem, finite element models of the myocardium were constructed, from isotropic, initially spherical, membrane models to realiHowever, the mechanical properties depend on the finite element model and its validation. Thus, techniques allowing the direct measure of these properties from medical imaging were introduced. Magnetic resonance elastography was proposed with specific gradient-echo sequences to reach small echo times and low excitation frequencies adapted for the myocardium-20. HoweThere is an incremental utilization of multi-parametric magnetic resonance imaging (MRI) for cardiac tissue characteristics and function. Maps of the longitudinal relaxation time T1 of the myocardium after injection of a contrast product allowed quantifying changes in heart failure models, reflecting tissue fibrosis. Higher Porcine hearts (n=12) were obtained from a local slaughterhouse  within 2 hours of death. A square sample of 10 cm*6 cm*4 cm was dissected from the left ventricular myocardial tissue of each isolated heart and placed in a chamber filled with a tyrode saline solution  at room temperature. Each sample was submitted to a multi-parametric MRI acquisition 4 to 6 hours after the tissue preparation, followed by a uniaxial tensile test one hour after the MRI acquisition.2. ADC and FA were calculated as described previously[The chamber was placed within the head coil of a 3 Teslas whole body system (Philips Achieva X-Series) and a single slice, 5 mm thick, was taken centered within the tissue sample. Images for the quantification of T1 and T2 were acquired using a multiple inversion recovery turbo spin-echo sequence for T1  and a multi-echo turbo spin-echo sequence for T2 . T1 and T2 weviously-44.The mean and standard deviation of T1, T2, MTR, FA and ADC were calculated over a square region of interest (ROI) chosen in the middle of the tissue. The sensitivity of the determination of the mean MRI parameters over the ROI to the ROI location within the slice was very low, due to a spatially uniform signal, whatever the image weighting  and independent  variables to verify our hypothesis. In order to account for potential interaction between MR parameters, a principal component analysis was used to convert the set of possibly correlated variables into a set of linearly uncorrelated variables. The data were rendered to Z-values by subtracting the individual results from the group’s average, and dividing by the calculated group’s standard deviation. The covariance matrix and its eigenvectors and eigenvalues were computed. The cumulative energy content for each eigenvector was used to select a subset of eigenvectors as basis vectors. The source data were then converted into the new basis. The first principal component (F1) has the largest possible variance, and each succeeding component  in turn has the highest variance possible under the constraint that it is orthogonal to the preceding components. All statistical tests were performed using XLSTATS . All results were expressed as Mean±SD and the significance of all tests was set to p≤0.05.All parameters measured Table  showed aMulti linear regressions showed that only 45% of E can be explained by the MRI parameters T1, T2, T2*, MTR, FA and ADC (Equation 1). The highest variance inflation factor was attributed to T2 when the regression was done on the 6 MRI parameters and to T2* when the regression was done on the remaining 5 MRI parameters (without T2). The multiple linear regression done after removing T2 and T2* (Equation 2) showed that all parameters had small and equivalent variance inflation factor and that the coefficient of determination did not change significantly (42%).The principal component analysis reduced our 7 variables  to two principal components F1 and F2 with a cumulative variability of 63%, which increased to 80% when considering the third principal component F3. The representation of the 7 variables in the  plane Figure-a showedThe principal component analysis reduced the 5 variables  to two principal components F1 and F2 with a cumulative variability of 67%, which increased to 81% when considering the third principal component F3. The representation of the 5 variables in the  plane Figure-b showedWe confirmed our hypothesis that a relationship exists between the Young’s modulus and the MRI parameters of the left ventricular myocardial tissue, and that this relationship may be in part non linear. Principal component analysis is very useful to reduce the dimensionality of a data set by projecting high dimensional data into a lower dimensional space. For the first time to our knowledge, a multi-parametric MRI acquisition composed of relaxation times mapping, magnetisation transfer and diffusion tensor imaging followed by a mechanical test in traction were performed on fresh porcine cadaveric hearts.Hyperelastic properties or coefficients of the exponential stress-stretch relation were reported from bi-axial traction tests performed on bovine heart samples, but the stress-stretch curves showed various Young’s moduli from 2-7 kPa-49 to 15The relaxation times we measured in this study on the isolated porcine left ventricular wall tissue were in the same range as the ones reported in the literature on animals or humans. Relaxography of excised rat myocardium showed T1 values of 907±77 ms, T2 values of 32±6 ms and T2* values of 32±6 ms. T2 valuThe relationship found between the Young’s modulus and the MRI parameters is the basis for the development of an indirect tool for the in vivo evaluation of the mechanical properties of cardiac tissues. However, these relationships vary between biological tissues and the degenerative state of the tissue. Equivalent experiments were done on intervertebral discs and showed that 45 to 80% of the Young’s modulus, the aggregate modulus, the radial permeability and the axial permeability can be explained mostly by MT and diffusion sequences. On the There were some limitations to this study which warrant further investigations. The low number of tissue samples was due to the difficulty to obtain the animals’ heart within two hours of death from the slaughterhouse. Our strict observation of the 2-hour window, in contrast, permitted the uniformity of the test results however. Another limitation relates to the chamber used for the MRI acquisition, which was manufactured in acrylonitrile butadiene styrene by rapid prototyping (fused plastic deposit). The limit of this method is that small air bubbles can be trapped during the fused plastic deposit, even if high-density presets are used. Nevertheless, artifacts on the relaxation time images were removed using a filter that suppresses high values . For the diffusion images, the use of a multi-shot echo-planar-imaging sequence decreased the distortion induced in the images by the air bubbles. Diffusion tensor imaging is often limited by a lower signal to noise ratio than in relaxation time imaging, but an estimated signal to noise ratio of 105 for our b=0 image confirms the reliability of our ADC and FA measures in the cardiac muscle tissue. From an analytical perspective, the mechanical behaviour of the cardiac muscle tissue is known to be hyperelastic-15 whichin-vivo sensitivity of MTR measurements to infarct and inflammation was proved[in-vivo remains challenging, but the feasibility has already been demonstrated and should be available in the near future. Thus our method could be transferred to in an in-vivo study in which the mechanical properties as determined by multi-parametric MRI could be compared to the mechanical properties as determined from cine-MRI or cine-tagging-MRI associated to finite element modeling[In vivo relaxometry of cardiac tissue is a well established method already used in clinical applications-30. The s proved. Howevermodeling-11.in vitro experiments will now allow us focused in vivo testing on healthy and infracted hearts in order to determine useful quantitative MR-based biomarkers. Based on our data it is also possible now to perform longitudinal in vivo testing on ischemic and revascularized hearts. Future directions of our laboratory aim for to better understand and to implement novel MRI parameters as biomarkers of myocardial viability and potential prognostic scoring of myocardial relaxation and contraction. The next experimental step will verify the in vivo application of this technique: the data from an in vivo multi-parametric MRI acquisition on healthy and infracted pigs will be compared to the data from the same MRI protocol performed on the same animals after euthanasia, followed by cyclic mechanical tests and biochemical tests.The proposed multi-parametric MRI protocol associated to principal component analysis is a promising tool for the evaluation of mechanical properties within the left ventricular myocardium. Our The authors declare that they have no competing interests.DP proposed the design of the study, carried out the data analysis, discussed the results and drafted the manuscript. ND participated to the results discussion and revised the manuscript. AF carried out the experiments. DC participated to the design of the study and the statistical analysis and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/13/24/prepub


The physician should look upon the patient as a besieged city and try to rescue him with every means that art and science place at his command.  ~ Alexander of Tralles.Science of medicine (and less of art) has progressed tremendously over the last few decades and engineering innovations have constantly changed the way we used to treat a patient. The field of cardiology is the best example of how technology has invaded into a human body making interventions a lot easier and safer. Cardiac pacing devices which initially were designed to treat bradycardia, have now found place for treatment for ventricular arrhythmia, heart failure and for prevention of sudden cardiac arrest. With increasing number of patients having cardiac disease and with the ever expanding indications of device therapy in clinical practice, the numbers of patients who are undergoing device therapy is expanding exponentially.Based on knowledge of inadequacies from prior implant data, cardiac pacing devices and related hardware are constantly undergoing refinement and are continuously being upgraded to being better and safer each time. Lead is placed in the right atrial appendage for atrial pacing and right ventricular apex or septum for right ventricular pacing for most of the patients through the axillary/subclavian/cephalic venous access. The pulse generator is kept most commonly in the subcutaneous or submuscular pocket in the pectoral region.  Active fixation lead (screw in lead) or passive fixation (tined) leads are selected based on patient's disease, need to do special site pacing or purely on operator preference. Pacing in the right atrial free wall, interatrial septum, right ventricular outflow, His bundle and left ventricle requires greater understanding of anatomy and/or training in using appropriate hardware and techniques for appropriate lead placement. Occasionally surgeons help needs to be taken for epicardial lead implantations. -3Though implantation of cardiac pacing device is now a safe time tested procedure, complications related to implantation, when enumerated are many, but occur in about 5.7% of patients and can be grouped as either procedural, component or biophysical interface related problems.-3 IntuitCommonly occurring complications of percutaneous venous access and blind subclavian puncture are subclavian artery puncture, pnuemothorax, hemothorax and hemo-pneumothorax. Lacerations of subclavian artery, nerve injury, thoracic duct injury, chylothorax and lymphatic fistula have occasionally been described. Contrast venography-guided venipuncture, ultrasound-guided puncture and an extra-thoracic subclavian puncture may decrease such complications and fluoroscopy time. Though cAcute complications of lead placement include thromboembolism (air/clot), arrhythmia, tricuspid regurgitation due to damage to the valvular apparatus and chamber perforation associated with or without cardiac tamponade. Left ventricular lead placement presents special challenges and complications due to need for coronary sinus cannulation and placement of a lead in a desired vein. Lead displacement with rise in thresholds, loss of pacing, diaphragmatic pacing and chamber perforation, pericarditis with or without cardiac tamponade can occur either immediately or at a later date. Misplacement of a lead is very uncommon, though described . ,4,7Device related complications include battery failure and pulse generator circuit failure, lead failure, conductor coil fracture and insulation failure.  ManufactAxillary vein thrombosis is rare occurring in 0.5-1% of cases. Partial venous obstruction in the great veins is almost a rule and occurs to some degree in up to 100% of cases. Clinically, pulmonary embolism however is extremely rare. Partial or silent inconsequential thrombosis is considered extremely common but generally of no clinical significance.  Pain at Pocket related complications like pocket hematoma, wound dehiscence, migration, erosion, pain and infection are well known and almost all who perform the procedure routinely have come across varying severity of such complications.  TwiddlerIf not vigilant, recognition of uncommon complications like a contralateral pneumothorax due to a right atrial micro-perforation by an atrial screw in lead described by Syamkumar et al in the issue of this journal sometimes can get delayed. Delayed Follow up of patients needs to be done regularly with cardiac devices and should be emphasized in all patients who receive them. It is not only necessary for optimizing battery life, but also to detect complications early related to the device or the biophysical interface so that correction can be done before significant symptoms develop. The case report by Garg et al presents an interesting patient, who after initial implantation never came for follow up, and presented with end of life of pulse generator and a chronic granulomatous mass over the incision site described due to hypersensitivity to non-absorbable suture material.  Ideally Atypical complications can occur. Complications though unavoidable, its manifestations can be minimized by early recognition and appropriate treatment. The absolute number of complications that we may see in the near future is going to increase, though the percentage of complications decrease with increase in the operator experience and better hardware, as absolute number of implantations occurring are increasing. Till the day, when advances in bio-technology would change the way we implant cardiac pacing devices for treatment of bradycardia, heart failure, ventricular tachycardia and for prevention of sudden cardiac arrest, we may still continue to face complications related to the interventions we do.


In clinical routine, quantification of myocardial strain using CMR tagging is currently the gold standard. Additional pulse sequences for the generation of tagged images and specialized software for the quantification of myocardial strain is necessary, so that alternative ways using conventional steady-state-free-precession (SSFP) sequence images would be preferable. This advantage may be ensured by feature tracking imaging algorithm, a novel method of two-dimensional deformation analysis.To quantify myocardial deformation with two-dimensional feature tracking cardiac magnetic resonance (CMR) in patients with heart failure due to non-ischemic cardiomyopathy and in healthy controls.Eighty-eight patients with dilated cardiomyopathy and thirty healthy subjects were examined in a 1.5T CMR-scanner. SSFP cine sequences of the four chamber view and mid-ventricular short axis view were analyzed using feature tracking imaging software . Generated parameters of the myocardial quantification were circumferential and longitudinal strain, respectively. Furthermore, patients were divided in subgroups classified by left-ventricular ejection-fraction LV-EF≤35% and EF>35% and in patients with the presence or absence of late-gadolinium enhancement (LGE), respectively.In patients with dilated cardiomyopathy, close correlation were observed for the LV-EF with circumferential strain  and with longitudinal strain , respectively. Regression analysis showed also high correlation between NT-proBNP and circumferential strain . Furthermore, significant differences of circumferential and longitudinal strain parameters were observed between healthy volunteers and patients with LV-EF>35% and with LV-EF ≤35% (p<0.0001). In addition, patients with LGE yielded significant lower circumferential and longitudinal strain values, compared to those without LGE .Feature tracking imaging determines global myocardial function in patients with dilated cardiomyopathy and provides further insight into the underlying remodeling processes. Further investigation is necessary to analyze the impact of this new method on clinical outcome.none


Various conventional methods are used for functional evaluation and risk stratification in heart failure. A combined index of global myocardial performance called the Tei index has been described. The aim of this study was to evaluate the correlation of the Tei index with other conventional indices of systolic and diastolic function among Nigerians with hypertensive heart failure.Fifty-five subjects with hypertensive heart failure and 30 controls were examined, a clinical history was taken, and echocardiography was performed on them. The subjects were categorised into four groups based on their ejection fraction . The Tei index was calculated as the sum of the isovolumic relaxation and contraction time, divided by the ejection time. Statistical analysis was done using SPSS 16.0.p < 0.005). The Tei index also increased with the severity of the heart failure and was inversely correlated with ejection fraction  and fractional shortening . It was directly correlated with mitral E/A ratio , left ventricular internal diastolic dimension , left ventricular internal systolic dimension  and deceleration time .The Tei index was significantly higher among subjects with hypertensive heart failure compared with the controls (0.91 ± 0.33 vs 0.28 ± 0.16, The Tei index correlated significantly with other conventional indices of systolic and diastolic function among Nigerians with hypertensive heart failure. It can be used as a risk-stratification index similar to other traditional indices of systolic and diastolic function. Heart failure worldwide is increasingly becoming a serious public health concern as the population continually ages and the risk factors for heart failure are increasingly prevalent.Heart failure is associated with significant morbidity and mortality.Currently, echocardiography is the single most useful non-invasive investigation used in the risk stratification of subjects with heart failure.The Tei index was introduced in 1995.The Tei index has been shown to correlate with other indices of systolic and diastolic function in subjects with heart failure, dilated cardiomyopathy, amyloidosis and congenital heart disease in other populations.Fifty-five consecutive subjects with a clinical diagnosis of hypertensive heart failure were included in this study. Thirty age- and gender-matched controls with a similar mean age were recruited as controls. They were patients’ relatives and hospital staff who gave their consent to participate in the study.Congestive heart failure was clinically diagnosed by the presence of related symptoms of left and/or right heart failure according to the Framingham criteria. Hypertensive heart failure was diagnosed by ascertaining a previous diagnosis and treatment with antihypertensive therapy and the presence of peripheral stigmata of hypertension, such as locomotor brachialis, thickened arterial wall, cardiomegaly and loud aortic component of the second heart sound. All of these patients were on combination therapy including medications such as diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aspirin or warfarin.Patients with diabetes, nephrotic syndrome, renal failure, present or past history of liver disease, and stroke were excluded from the study. Patients with echocardiographic evidence of valvular heart disease, dilated cardiomyopathy and restrictive cardiomyopathy as well as those with incomplete echocardiographic examinations and poor image windows were also excluded.All subjects were examined and a clinical history was taken. Two dimensional (2D), M-mode and Doppler echocardiography were done in the left lateral decubitus position using a 3.5-MHz probe, according to standard recommendations of the American Society of Echocardiography.In our laboratory, the intra-observer concordance correlation coefficient ranged from 0.80 to 0.96 while that of the inter-observer concordance ranged from 0.79 to 0.97. Hypertensive heart failure subjects were categorised, based on the ejection fraction, into normal ejection fraction, mild heart failure (ejection fraction 45–55%), moderate heart failure (ejection fraction 35–45%) and severe heart failure (ejection fraction < 35%). The Tei index was defined as the sum of the isovolumic relaxation time and isovolumic contraction time, divided by the ejection time obtained from the left ventricular inflow and outflow, as shown in 15t-test and chi-square test as appropriate. Statistical relationships between Doppler echocardiography measurements, Tei index and echocardiography-derived variables were done by correlation analysis. A p-value < 0.05 was taken as statistically significant.Ethical approval was obtained for the study. Statistical analysis was done using the Statistical package for Social Sciences 16. 0 (Chicago Ill). Data were summarised as means ± standard deviation (quantitative) and proportions and percentages . Comparison between groups was done by the independent The mean age of the subjects with hypertensive heart failure was 57.8 ± 14.2 years (age range 42–87 years) and comprised 26 females (47.3%), compared to 56.4 ± 18.6 years, with 19 females  for the control group. They were well matched in age distribution and gender. Hypertensive heart failure patients were receiving combination therapy including at least diuretics, ACE inhibitors and aspirin/warfarin.p < 0.005, respectively). Posterior wall thickness, inter-ventricular septal thickness, left ventricular internal dimension in diastole and systole, and left atrial dimensions were higher among subjects with hypertensive heart failure than control subjects. The Tei index was significantly higher among hypertensive heart failure subjects than controls .et al. and Amoah et al., with hypertension remaining the commonest cause.17Heart failure is a major and growing public health concern globally. The aetiologies of heart failure in Africans include hypertension, cardiomyopathies and rheumatic heart disease, as reported by Ntusi This study shows that the Tei index of myocardial performance is significantly different between patients with hypertensive heart failure and normotensive subjects. It also shows that the higher the degree of systolic dysfunction, the higher the Tei index. Another important finding was that the Tei index correlated significantly with other conventional indices of systolic and/or diastolic dysfunction among Africans with hypertensive heart failure. It may therefore be a clinically useful index of overall dysfunction among black Africans with heart failure, in a similar way that ejection fraction, fractional shortening, deceleration time and isovolumic relaxation time are useful for risk estimation, treatment evaluation and prognosis in subjects with heart failure.Traditionally, assessment of left ventricular function has focused on measurement of ejection fraction and diastolic indices using Doppler measurements for risk stratification and treatment evaluation.The Tei index is a function of cardiac intervals derived from ejection time, contractility and relaxation period. It therefore indicates combined systolic and diastolic dysfunction and appears to be a more ideal test for overall dysfunction in heart failure. It has been shown to be independent of ventricular loading conditions, is easily reproducible, and assesses the overall function of the heart.24The Tei index is non-invasive and easily obtainable. It has also been shown to have prognostic significance in subjects with heart failure.27Several authors have argued that some degree of systolic and diastolic dysfunction coexist in almost all patient with heart failure.As promising as the Tei index is, it is not yet clear whether it has any role in the aetiological classification of heart failure or in differentiating systolic from diastolic heart failure. These could be assessed by further prospective studies.The Tei index correlated well with conventional indices of systolic and diastolic dysfunction in subjects with hypertensive heart failure. It may be an additional tool for risk stratification, treatment evaluation and prognosis in black Africans.


The aim of this study was to assess the effectiveness of cardiac resynchronization therapy (CRT) by intracardiac delay optimization using echocardiography. Sixty-five patients were implanted with a CRT device randomly assigned to receive simultaneous biventricular pacing or echo-optimized sequential CRT. Forty-two patients were defined as responders and 23 patients were classified as non-responders. During a 12-month follow-up period, the positive response rate, QRS duration, New York Heart Association class, mitral insufficiency grade, left ventricular end-systolic volume and LV end-diastolic volume were similar in the optimized and non-optimized groups (P>0.05), whereas 6-minute walking distance, quality-of-life score, left ventricular (LV) ejection fraction and aortic velocity time integral were significantly improved in the optimized group (P<0.05). The baseline QRS durations of the responders and non-responders were similar (P>0.05), whereas heart failure aetiology, clinical and echocardiographic measurements showed significant differences (P<0.05). The mean decrease in QRS duration after 12 months of CRT used for separating responders and non-responders was significantly different (P<0.05), and significant differences were observed in the mean decrease of QRS duration between responders and non-responders (P<0.05). Echocardiographic optimization may further improve the effectiveness of CRT. Moreover, severe mitral regurgitation and greater LV volume are likely to indicate a poor response to CRT. Despite improvements in pharmacologic treatment, many patients with heart failure have severe and persistent symptoms and their prognosis remains poor ,2. Such Despite current selection criteria, up to 40% of patients treated with CRT do not benefit ,13. It hIn this prospective study, our center analyzed 65 patients, 46 patients implanted with CRT-P (biventricular pacemakers) and 19 patients implanted with CRT-D (biventricular cardioverter-defibrillators), from January 2003 to December 2008. Patients were selected according to current guidelines for CRT ,17: i) sAll patients underwent a clinical examination and echocardiographic evaluation prior to CRT and after long-term follow-up. Evaluation of clinical status included assessment of NYHA class and patient’s quality-of-life score. The quality-of-life score was assessed using the Minnesota Living with Heart Failure Questionnaire, which contains 21 questions concerning a patient’s perception of the effects of heart failure on daily life activities . QuestioPatients with an improvement of ≥1 grade in NYHA class were considered clinical responders to CRT ,21. PatiDuring pacemaker implantation, the LV pacing lead was inserted transvenously via the subclavian route . After aAll echocardiographic data were analyzed offline by the same investigator, blind to all programming information. For each parameter, three consecutive cardiac cycles were analyzed and the average value was taken.The ultrasound system used was a Vivid 7 . The LVEF, LVESV and LV end-diastolic volumes (LVEDV) were calculated according to the biplane modified Simpson’s rule . The degThis study protocol was based on echo-guided optimization of AV and VV delay performed within 48 h of implantation and then repeated during the follow-up for patients in the optimized group. The heart rate was stable (±5 bpm). AV delay optimization was performed during simultaneous biventricular pacing. AV delays were analyzed between 60 and 200 msec, in steps of 10 msec. Utilizing pulsed Doppler analysis of the transmitral flow, the programmed AV delay that provided the longest LV filling time and EA interval without interruption of the A-wave was chosen. VV delay optimization was performed following AV delay programming. We analyzed VV intervals ranging from −80 msec (LV pacing first) to +80 msec (right ventricular pacing first), in steps of 10 msec. VV delay was optimized by measuring VTIa and optimal VV delay was determined by maximizing VTIa.2 test for categorical variables. Continuous variables within and between groups were compared using two-sided paired and unpaired Student’s t-test. Categorical data were compared using the Cochran-Armitage test for trends. A two-tailed P<0.05 was considered to indicate a statistically significant difference.The data were analyzed using the statistical software program SPSS V.12.0.1. Summary data are expressed as mean ± standard deviation (SD) or percentage of patients. The comparison of the baseline characteristics between the groups was performed with the independent sample t-test and the χNo significant differences in the baseline variables between the optimized and non-optimized groups were observed . Two patAs shown in During the 12-month follow-up, the functional capacity and echocardiography measurements demonstrated significant improvement in the responder group  and the mean decreases in QRS duration for the responder and non-responder groups were significantly different  is included in the selection criteria for CRT –18.We studied the value of QRS duration prior to implantation of a CRT device in 65 patients to evaluate the level of response. In addition, we evaluated the decrease in QRS duration after 12 months of CRT to predict the response to CRT. The present study aimed to evaluate the predictive value of QRS duration for clinical and echocardiographic responses to CRT in a selected study population. No significant differences were observed in QRS duration at baseline between the responders and non-responders; however, significant differences were observed in the mean decrease of QRS duration between the two groups at 12-month follow-up. A correlation was observed between the change of baseline QRS duration and improvement in exercise capacity, functional status, quality-of-life score, LVEF and LV volume at 12-month follow-up. Moreover, our study demonstrated that, besides the change of QRS duration, ischemic heart disease, impaired LV function, severe MR and greater LV volume were predictors for non-response; patients with those characteristics were likely to have a less satisfactory response to CRT. Accordingly, it has been suggested that the duration of the QRS complex at baseline may not be the optimal criterion for selection of patients for CRT.This is a small pilot study performed in a single center. Due to the small number of patients, no multivariate analysis of the several parameters and no calculation of predictive values could be performed. We used formerly popular parameters that were relatively easy and not time-consuming to examine; however, measurement of these clinical parameters is subjective and imprecise with low reproducibility and high inter- and intra-observer variability, as is known from the PROSPECT study .The modified Simpson’s rule was used for LV volume calculation, which may not be optimal for the spherical shape and asymmetrical contraction in the hearts examined. With the discoordinated contraction in left bundle branch block (LBBB), the smallest cavity area may not truly represent the end of systole, as late activated areas may still be contracting. The choice of echocardiographic parameters should include parameters of three-dimensional echo as well as parameters of radial and circumferential asynchrony. This was not included since the software and equipment was not available for all patients.Currently, a clear definition of response to CRT is lacking. Clinical and echocardiographic end points are interchangeably used to determine the response to CRT. In the present study, clinical and echocardiographic variables were used to define the response to CRT. Importantly, there is a discrepancy between clinical and echocardiographic responses to CRT. However, despite the growing emphasis on several criteria for the response to CRT, large prospective studies are required to determine which parameter is best for selecting patients for CRT.


Controversy remains with regards to the optimal site for right ventricular (RV) pacing, with mounting evidence that RV apical pacing leads to accelerated deterioration in left ventricular systolic function both on the background of normal as well as already impaired ventricles. RV septal pacing is conceptually associated with a more physiological activation pattern and as such should confer advantages over apical pacing. However, echocardiographic studies regarding its benefit have been conflicting. The recent introduction of MR-conditional pacing systems, without iso-centre restriction, allows investigation of this fundamental clinical question with the more accurate and reproducible modality of CMR. MAPS is a prospective double blinded cross-over study using multiparametric CMR to determine acute and intermediate effects of RV apical versus septal pacing in patients post atrio-ventricular (AV) node ablation for AF. Here we present preliminary findings of the first acute studies.Eleven patients undergoing AV node ablation and pacemaker implantation as a treatment for atrial fibrillation were prospectively recruited. Each patient received a MR-conditional pacing system (St Jude Accent) with 2 ventricular leads (Tendril MR); one placed at the RV apex and one placed at the mid-septum/RVOT transition. The AV node ablation ensured 100% pacing. CMR (1.5T) was performed 13+/- 1 week after implantation and included aortic and pulmonic phase-contrast velocity mapping during both apical and septal pacing modes. The maximum delay in time to peak strain of opposing wall segments was calculated from 4chamber SSFP cine images using an endocardial feature tracking software package  and used as a marker for dys-synchrony.6 patients were female, average age of the cohort was 68±7. 3. There was trend towards higher mean aortic forward flow volume during septal pacing (72.7±18.3 ml) compared to apical pacing . Likewise, there was a trend towards higher mean pulmonic forward flow volume during septal pacing (112.4±41.6mL) compared to apical pacing . These hemodynamic improvements occurred on the background of a significant reduction in maximum time to peak strain of opposing wall segments for septal pacing (162 ms ±119 ms) compared to apical (246 ms ±110 ms) pacing (p=0.017).These preliminary data suggest that RV septal pacing, by means of a more physiological electromechanical activation pattern, leads to acute hemodynamic benefits. The on-going MAPS trial promises to provide answers with respect to acute and intermediate term benefits in a sufficiently powered and appropriate study design.The MAPS study is supported by a restricted Grant from St Jude. Dr Ainslie is supported by St Jude Medical. Dr Miller is supported by the National Institute of Health Research. Dr Schmitt is supported by the Greater Manchester Comprehensive Local Research Network funding.


Systemic sclerosis (SSc) is characterised by multi-organ tissue fibrosis including the myocardium. Diffuse myocardial fibrosis can be detected non-invasively by T1 and extracellular volume (ECV) quantification, while focal myocardial inflammation and fibrosis may be detected by T2-weighted and late gadolinium enhancement (LGE), respectively, using cardiovascular magnetic resonance (CMR). We hypothesised that multiparametric CMR can detect subclinical myocardial involvement in patients with SSc.19 SSc patients  and 20 controls  without overt cardiovascular disease underwent CMR at 1.5T, including cine, tagging, T1-mapping, T2-weighted, LGE imaging and ECV quantification.Focal fibrosis on LGE was found in 10 SSc patients (53%) but none of controls. SSc patients also had areas of myocardial oedema on T2-weighted imaging (median 13 vs. 0% in controls). SSc patients had significantly higher native myocardial T1 values , larger areas of myocardial involvement by native T1 >990 ms (median 52 vs. 3% in controls) and expansion of ECV , likely representing a combination of low-grade inflammation and diffuse myocardial fibrosis. Regardless of any regional fibrosis, native T1 and ECV were significantly elevated in SSc and correlated with disease activity and severity. Although biventricular size and global function were preserved, there was impairment in the peak systolic circumferential strain  and peak diastolic strain rate  in SSc, which inversely correlated with diffuse myocardial fibrosis indices.Cardiac involvement is common in SSc even in the absence of cardiac symptoms, and includes chronic myocardial inflammation as well as focal and diffuse myocardial fibrosis. Myocardial abnormalities detected on CMR were associated with impaired strain parameters, as well as disease activity and severity in SSc patients. CMR may be useful in future in the study of treatments aimed at preventing or reducing adverse myocardial processes in SSc. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterised by vascular dysfunction and multi-organ fibrosis. The heart is one of the major organs commonly involved in SSc, with an estimated clinical prevalence of 15-35% ,3. In thDiffuse myocardial fibrosis is the pathological hallmark of cardiovascular involvement in SSc, reported in up to 80% of cases in autopsy studies , and is Cardiovascular magnetic resonance (CMR) can non-invasively detect myocardial inflammation and fibrosis. T2-weighted imaging can identify areas of myocardial oedema, and late gadolinium enhancement (LGE) imaging can identify areas of focal fibrosis in patients with SSc ,12. HoweWe therefore hypothesised that T1 and ECV quantification would reveal subclinical myocardial involvement in asymptomatic SSc patients with no known cardiovascular involvement when compared to controls of similar age and sex. We also sought to investigate the relationship between myocardial findings on CMR and indices of SSc activity, severity and chronicity, and early signs of myocardial dysfunction.This was a prospective study enrolling unselected patients with SSc (n = 19), without any known CVD. Patients were recruited from 5 hospitals in the Thames Valley, United Kingdom  between January 2011 and December 2012. The SSc patients were between the ages of 18 and 65 years, and were diagnosed with SSc using the 1980 American College of Rheumatology criteria . ExclusiCMR studies were performed using a single 1.5 T MR system . A 32-channel phased-array chest coil was used for all data acquisition, except for STIR imaging, for which the body coil was used. A complete stack of short axis images were obtained during breath hold and cardiac gating for cine, precontrast (native) T1 mapping, T2-weighted and LGE imaging. T1 mapping was performed using the ShMOLLI (Shortened Modified Look-Locker Inversion Recovery) sequence , and T2 All CMR images and maps were analysed offline in a blinded fashion.3). Left atrial diameter was measured in the LV outflow tract (3-chamber) view.Analysis of left ventricular ejection fraction was performed using Argus software . Left ventricular (LV) short axis epicardial and endocardial borders were manually contoured at end-diastole and end-systole. LV end systolic (LVESV) and end diastolic (LVEDV) volumes were used to calculate stroke volume (SV) and ejection fraction (EF) – (EF = SV/EDV). Myocardial mass was also calculated by subtracting the endocardial volume from the epicardial volume, based on prior knowledge of myocardial specific gravity  by aligning a grid to the myocardial tagging planes in end-diastole. End-systole was determined visually, and tags are adjusted at each frame through the cardiac cycle. From the mid-short axis slice, peak circumferential systolic strain and peak diastolic strain rate were derived.myocardium:skeletal = SImyocardium/SIskeletalmuscle, as previously published [Quantitative analysis was performed by comparing the LV myocardium in short axis against adjacent skeletal muscle in the same slice, verified on a corresponding SSFP image. The T2 signal intensity (SI) ratio was calculated as T2 SIublished . MyocardImages were evaluated qualitatively for the presence or absence, pattern  and regional distribution of LGE areas by three observers, each with at least 4 years of CMR experience. The detection of LGE was made by consensus of all 3 observers. In addition, endocardial and epicardial regions of interest (ROI) were manually contoured in the LGE images, together with a reference ROI in the anterior LV wall without visual LGE, and focal areas of LGE were defined quantitatively as those with SI ≥ 2.0 standard deviations above the mean SI of normal myocardium.Analysis of T1 mapping was performed as previously described . BrieflyConsistent with established methods of estimating myocardial ECV using a delayed postcontrast bolus protocol , we meas2 above the specified thresholds were considered relevant. This corresponds to 10 adjacent pixels for the STIR method, in accordance with currently proposed recommendations [Briefly, on dark-blood T2W images, oedema was diagnosed when myocardial T2 SI is ≥ 1.9 compared to that of skeletal muscle ; on T1 mndations , to reduTwo-dimensional, M-mode and Doppler echocardiograms were acquired using a Toshiba Artida 4D system . Images were acquired with the patients in the left lateral decubitus position. Primary measurements of mitral inflow included the peak early filling (E-wave) and late diastolic filling (A-wave) velocities, the E/A ratio, deceleration time (DT) of early filling velocity, which were derived by placing the cursor of the pulsed wave Doppler in the LV, above the tips of the mitral valve, to display the onset of mitral inflow, using a 5 MHz transducer. The passive LV filling (E’-wave) was measured from the pulsed wave tissue Doppler of the mitral septal annular velocity. Right ventricular systolic pressure was based on measurement of maximal tricuspid regurgitation velocity and applying the modified Bernoulli equation before addition of the estimated right atrial pressure (5 mmHg).Disease activity was assessed using the Valentini disease activity index (VDAI) of the European Scleroderma Study Group criteria for disease activity in SSc , which iSSc patients were classified as having either diffuse (n = 10) or limited cutaneous SSc (n = 9). The severity of skin fibrosis was quantified using the modified Rodnan skin score (mRSS) , a measuS coefficient, as appropriate. All statistical tests were two-tailed and a p-value of less than 0.05 was considered statistically significant. All analysis was performed using SPSS version 20 .Normality of data was tested using the Kolmogorov-Smirnov test. Normally distributed data are presented as mean ± standard deviation (SD) or, where highly skewed, as median (interquartile range); non-parametric data are presented as numbers (percentages). The chi-square test or Fischer’s exact test was used to compare dichotomous data. The unpaired Student t-test  or Mann-Whitney U test (for non-parametric data) was used to compare continuous variables between SSc patients and controls, as appropriate. Post-hoc Bonferroni correction was used to explore whether there were differences between the SSc patients and controls. Any segmental data were averaged on a per-subject basis before group comparisons to control for clustering of segments within each subject. Bivariate correlations were assessed using the Pearson R or Spearman RThe SSc patients were well-matched with controls for age, sex and comorbidities and only a small minority of patients were on regular disease modifying anti-rheumatic drugs Table . Most pa-1, p < 0.001) compared to controls. Evidence of impaired diastolic function was also confirmed on echocardiographic assessment, which showed abnormal relaxation indices in SSc patients .There was no significant difference in LV size, mass and ejection fraction between SSc patients and controls Table . DespiteWe found no difference in RV size and global systolic function between SSc patients and controls. While right ventricular systolic pressures were higher in the SSc patients , they were within normal limits for all study subjects, excluding the presence of significant pulmonary hypertension in this cohort.Confirming previously published data, we found increased incidence of LGE in SSc patients compared to matched controls (53% vs. 0%), as shown in Table On conventional dark-blood T2-weighted imaging, while there was no significant difference in the overall global myocardial T2 SI ratio in SSc patients compared to controls , SSc patients had significantly more areas of focal myocardial oedema within the left ventricle .Native T1 mapping was performed in all SSc patients; and postcontrast T1 mapping was done in 14 of the 19 SSC patients, as 5 patients were not consented for gadolinium. SSc patients had significantly higher average myocardial T1 values  and larger areas of myocardial involvement detected by native T1 mapping . SSc patients also had significantly higher λ  and expanded ECV . Also, there was no difference in postcontrast T1 values between controls and SSc patients with LGE, despite the significant differences in native T1 and ECV. Importantly, between SSc patients without LGE and SSc patients with LGE, there was no difference in native T1, postcontrast T1, λ, and ECV, indicating that the increase in ECV was not driven by the presence of LGE Table .When SSc patients were stratified according to limited cutaneous or diffuse SSc, only native T1 mapping and ECV quantification were able to further differentiate the two subgroups according to myocardial involvement Table : patientS 0.60, p = 0.04); native T1 and mRSS , native T1 and SSc VDAI , native T1 and serum CRP  as shown in Figure There was significant, moderate correlation of myocardial involvement detected by T1 and ECV to indices of SSc disease activity and severity: ECV and mRSS , ECV and SSc VDAI  and diastolic strain rate . Both native T1 and ECV correlated inversely with peak circumferential systolic strain  and diastolic strain rate , there were also areas of focal myocardial oedema or inflammation (as detected by T2-weighted imaging). Further, using more sensitive techniques such as native T1 mapping and ECV quantification, we were able to demonstrate even more areas of myocardial involvement in SSc patients than conventional CMR techniques can reveal, with SSc patients showing significantly larger areas of T1 abnormality and expanded ECV, which likely represent a combination of low grade inflammation and diffuse myocardial fibrosis that are well-described disease processes in this cohort. Interestingly, T1-mapping and ECV quantification were sensitive enough to further stratify myocardial involvement in patients with diffuse SSc compared to patients with limited cutaneous SSc, with the former showing significantly larger areas of myocardial T1 abnormality and ECV expansion. Finally, T1 and ECV measures were associated with subtle myocardial systolic and diastolic dysfunction. The results of this study suggest that CMR, particularly T1 and ECV quantification, can be used for early detection of subclinical myocardial involvement in SSc patients, potentially serving as an early screening tool before overt LV dysfunction or irreversible myocardial damage occurs.In historic autopsy studies, diffuse myocardial fibrosis has been reported as the pathological hallmark of cardiovascular involvement in SSc ,8. ChronMyocardial fibrosis is characterised by excessive deposition of extracellular matrix proteins, rich in collagen , which uNative (precontrast) T1 and ECV mapping are novel CMR markers that provide a quantitative measure of tissue characterisation without relying on relative signal comparisons . T1 mapsWe showed increased native T1 and expanded ECV in SSc patients without cardiovascular symptoms. It is difficult to separate how much of the increase in T1 was due to myocardial inflammation as opposed to diffuse myocardial fibrosis, as both would increase native T1 values . There was a degree of myocardial oedema as shown by results using T2-weighted imaging, but the areas of oedema detected are not directly subtractable from areas of abnormality detected by T1, since these are different techniques with different sensitivities and specificities for oedema . Native Despite the absence of global functional impairment, we found impaired peak circumferential LV systolic strain in SSc patients, in keeping with previous reports . There wT1 and ECV measures both correlated inversely with peak systolic strain and peak diastolic strain rate in SSc patients. Several reports  have confirmed that myocardial fibrosis precedes strain abnormalities and that fibrosis is a significant contributor to the pathogenesis of myocardial relaxation abnormalities ,41. NotaWe have found that both ECV and native T1 are useful for the assessment of myocardial involvement in SSc. In patients who are unable to tolerate gadolinium, native T1 may be used as a surrogate biomarker for myocardial fibrosis ,17, if oOur study has several limitations. First, the number of SSc patients included in this study is small; nevertheless the control group was well chosen and large significant differences in the parameters measured have been observed. Second, native myocardial T1 values may increase with myocardial oedema, myocardial infarction, myocarditis or amyloidosis ,34,35 anIn conclusion, subclinical myocardial involvement is common in SSc patients without cardiac symptoms, as measured by T2-weighted imaging, native T1, quantitative LGE and ECV measurement; and likely signifies a combination of myocardial inflammation and diffuse fibrosis which correlated with both SSc disease activity and skin fibrosis severity, as well as with subclinical impairment of systolic and diastolic strain despite the preserved LV ejection fraction. These findings support a mechanistic role for myocardial inflammation and possible diffuse fibrosis in preclinical as well as advanced SSc disease. The results of this study highlight key advantages of multiparametric CMR to track these preclinical changes, which may be useful in the clinical setting and possibly as surrogate endpoints for therapeutic trials. Finally, our data suggest that native T1 and ECV measurement may add incremental information to LGE focal fibrosis quantification, and that focal and diffuse fibrosis may reflect different underlying pathological processes.CMR: Cardiovascular magnetic resonance; CVD: Cardiovascular disease; ECG: Electrocardiogram; ECV: Myocardial extracellular volume; ESR: Erythrocyte sedimentation rate; LGE: Late gadolinium enhancement; LVEF: Left ventricular ejection fraction; mRSS: Modified Rodnan skin score; SSc: Systemic sclerosis; SI: Signal intensity; ShMOLLI: Shortened Modified Look-Locker Inversion Recovery; SSFP: Steady-state free precession; STIR: Short-Tau inversion recovery.Competing financial interests.We have no financial conflicts of interests to declare.Competing non-financial interests.US patent pending 61/387,591: SKP, MDR. SYSTEMS AND METHODS FOR SHORTENED LOOK LOCKER INVERSION RECOVERY (Sh-MOLLI) CARDIAC GATED MAPPING OF T1. September 29, 2010. All rights sold exclusively to Siemens Medical.US patent pending 61/689,067: SKP, MDR. COLOR MAP DESIGN METHOD FOR IMMEDIATE ASSESSMENT OF THE DEVIATION FROM ESTABLISHED NORMAL POPULATION STATISTICS AND ITS APPLICATION TO CARDIOVASCULAR T1 MAPPING IMAGES.All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.NABN, PMM, BPW, SN and TDK were involved in the study conception and design. NABN, JMF and TDK were involved in data acquisition. NABN, SKP, VMF, JMF, ABSR and TDK were involved in data analysis. NABN, SPK, VMF, SN and TDK were involved in data interpretation. All authors read and approved the final draft.


Simulation of bi-ventricular failure with pulmonary hypertension revealed inadequacy of LV support alone. These simulations motivate the implementation of an extremum tracking feedback controller to potentially optimize ventricular recovery.Lumped parameter models have been employed for decades to simulate important hemodynamic couplings between a left ventricular assist device (LVAD) and the native circulation. However, these studies seldom consider the pathological descending limb of the Frank-Starling response of the overloaded ventricle. This study introduces a dilated heart failure model featuring a unimodal end systolic pressure-volume relationship (ESPVR) to address this critical shortcoming. The resulting hemodynamic response to mechanical circulatory support are illustrated through numerical simulations of a rotodynamic, continuous flow ventricular assist device (cfVAD) coupled to systemic and pulmonary circulations with baroreflex control. The model further incorporated septal interaction to capture the influence of left ventricular (LV) unloading on right ventricular function. Four heart failure conditions were simulated (LV and bi-ventricular failure with/without pulmonary hypertension) in addition to normal baseline. Several metrics of LV function, including cardiac output and stroke work, exhibited a unimodal response whereby initial unloading improved function, and further unloading depleted preload reserve thereby reducing ventricular output. The concept of  But this neglects the pathological descending limb of the Frank-Starling response of the overloaded ventricle—beyond the limit of contractile reserve Lumped parameter models of mechanical circulatory support have been employed for the past two decades to simulate important hemodynamic couplings between a ventricular assist pump and the native circulation. In the modern era of continuous flow ventricular assist devices (cfVADs), such models have been used to identify algorithms for feedback control so as to adequately unload the native ventricle The current study therefore investigates the hemodynamics of mechanical circulatory support with a more accurate model of the failing heart, in which the ESPVR is a unimodal function. This model provides sufficient and necessary conditions for the existence of a finite, maximum cardiac power output. A lumped parameter simulation of the systemic and pulmonary circulation with baroreflex control was implemented numerically, encompassing a variety of cardiac pathologies, including combinations of LV and right ventricular (RV) failure, with and without pulmonary hypertension. The model further incorporates right-left ventricular interdependence through the inclusion of an intraventricular septum element: to capture the influence of mechanical coupling of the two ventricles through a shared septal wall A nonlinear time-varying lumped parameter model of the circulatory system, described previously by Ursino et al. Instantaneous ventricular pressure ons. See .) The syal data   as definTo simulate ventricular interdependence, mechanical coupling between the right and left ventricles through the interventricular septum was characterized by an interventricular elastance model developed by Chung et al. A model of a rotodynamic, continuous flow LVAD To simulate potential suction events caused by negative pressure within the LV, an additional nonlinear suction resistor A series of simulated experiments was conducted under normal conditions (no LV/RV failure) and four different pathological conditions The effect of the cfLVAD on the hemodynamics was evaluated in each of the five baseline conditions defined above. LVAD speed was increased from 6k RPM to 12k RPM in increments of 1k RPM and ventricular pressure-volume (PV) loops were composed for each, from which the following indices were evaluated: total CO , LAP, RAP, LV stroke volume . This was performed for the normal and four heart failure pathological conditions. The corresponding hemodynamic benchmarks are provided in Ventricular pressure-volume (PV) loops generated for each of the simulated conditions are shown in ons. See . Elevati2 body surface area The effects of LVAD support for each of the four pathological simulations are further illustrated in The introduction of moderate- to severe pulmonary hypertension to the condition of bi-ventricular failure  caused aThe hemodynamics were somewhat improved by reversing RVF; however pulmonary hypertension continued to limit the overall CO. See . Similar2). The simulation replicated this trend: as the LVAD speed was reduced from 10k to 6k RPM, the AP continuously increased with a slight increase of Continuous-flow LVADs have recently proven their efficacy in providing long-term circulatory assistance, reversing symptoms of heart failure and, in certain cases, facilitating cardiac recovery This study was designed to investigate the relationship of level of mechanical circulatory support upon hemodynamics and ventricular energetics, in the context of dilated heart failure. The main findings provided by a lumped parameter simulation are: (1) a rightward shift of the pressure-volume (PV) loop, (2) a concomitent decrease in LVESP, (3) increase of LVEDP and LVEDV, and (4) in the most severe cases of cardiac overloaded, the ventricle exhibits a paradoxical response to preload wherein both LVESP and stroke volume decrease with increasing preload.A novel feature of this model was the incorporation of a pathological ESPVR that represents the over-distended ventricle more accurately than a conventional, monotonically increasing function. The ventricular ESPVR has most commonly been regarded as linear, but in some cases has been represented by a quadratic function, flattening with high preload Due to limiting effect of the EDPVR, the use of a monotonically increasing ESPVR will not necessarily cause unbounded cardiac output. However, a monotonic model of the overloaded, decompensated ventricle is clearly inadequate for characterizing the therapeutic effect of decompression.It should be acknowledged that there are a variety of mechanisms that may be responsible for the descending portion of ESPVR. In the acutely overloaded heart, there is the possibility for energy starvation, leading to muscle exhaustion. increase stroke volume with decreasing preload. Mitral regurgitation is another likely condition presented in chronic dilatation due to the distortion of the mitral annulus. Reversal, or alleviation of volume overload, for example by diuresis, has been shown to extremal loading. This was identified as the degree of VAD support for which LV stroke work is maximized. Above this level of support, the incremental improvement in net cardiac output is diminished, and eventually reaches an asymptote, constrained by venous return and/or RV output. Although impossible to prove here, it is reasonable to hypothesize that this represents a speed set-point for feedback control that is advantageous to myocardial rehabilitation. While it may be controversial whether physiologic ventricular loading or cardiac exercise promotes reverse remodeling, there exists sufficient clinical evidence that chronic unloading results in myocardial disuse atrophy Within this context, the current simulation studies introduced a concept of The obvious implication is that under certain circumstances it would be undesirable to operate the LVAD at full support. This may appear contrary to clinical intuition: to place an artificial constraint on cardiac output. On the other hand, these simulations demonstrated that the incremental gain in pump output above the optimal speed was counteracted by a diminution of cardiac contribution, resulting in a zero-sum gain. Furthermore, there is growing evidence of the benefit of allowing the aortic valve to open periodically A further clinical consideration that would favor less-than-maximal LVAD output is the potential for exacerbating RV dysfunction Inasmuch as the ESPVR function is not static, but dependent on time-varying factors such as the progression/reversal of disease, inotropic state, duration of volume overload, etc., the model presented here is intended to be illustrative rather than definitive. The chosen point of extremal loading was somewhat arbitrary, as it would depend on the body mass index (BMI) as well as etiology and extent of dilatation. Hence, any mechanical circulatory support strategy based on this function should be personalized to a given patient. And since the function is time-varying, there is a need for continuous feedback control.This is however confounded by the unavailability of observable state variables  in the actual clinical setting. Therefore they must be inferred from readily measurable sources, such as the electrical signals from the VAD itself Apart from feedback control, the simulation model affords the opportunity to perform in-silico interventions, such as vasoactive drugs, diuretics, correction of mitral regurgitation, insertion of a right ventricular assist device, etc. It is also hoped that this simulation model may be employed to provide greater confidence for manual adjustment of pump speed, which is commonly avoided for fear of ventricular suck down, regurgitant flow, or ventricular overload.While the present model defines the point of overload in terms of end systolic volume, physiologically it would be more correct to define it in terms of a critical sarcomere stretch, hence end-diastolic volume. A model based on this premise would not be readily compatible with the mathematical formulation here, but could possibly be implemented in terms of a unimodal SWI-EDV model. However, resulting hemodynamic response to LVAD support would be equivalent; inasmuch as the latter relationship is defined implicitly, rather than explicitly.An additional limitation of the present model is omission of pathological vascular regulation that is common to end-stage heart failure. In lieu of an established rennin-angiotensin- aldosterone model, these regulatory effects could be introduced manually into the current baroreflex model in a future extension of this work. An additional aspect of cardiac failure that would be interesting to incorporate into a future study would be intra-ventricular dyssynchrony.This study made a best effort to assure the accuracy of the simulation model presented here by reference to various data sources from the literature. However, definitive validation will require data from actual patients receiving cfLVAD support that exhibit a spectrum of heart failure. This is the goal of an ongoing clinical study by our group. Until such corroborating data are available, the present study serves as a prototypical template upon which a clinical study may be designed.The future direction of this research will be to also develop extremum-tracking controllers Appendix S1Supporting material: Numerical representation of the left and right ventricles, septum, systemic and pulmonary vascular impedances; Kirchoffs set of thirteen state equations derived for the full cardiovascular model; Tables AI-AIV contains the parameter values and hemodynamic variables derived from the literature and used in the simulator under normal and different pathological conditions.(TIF)Click here for additional data file.