We tested the hypothesis that the apical myocardial mechanics differ from those of other ventricular segments in hypertensive patients with and without apical hypertrophic cardiomyopathy (ApHCM).We retrospectively studied hypertensive patients with and without ApHCM. Left ventricular longitudinal, circumferential, and radial strains were examined by two-dimensional speckle-tracking echocardiography at the basal, middle, and apical walls of the parasternal short-axis and apical 2-, 3- and 4-chamber views.Fourteen consecutive patients with hypertension and ApHCM and 14 patients with hypertension without ApHCM were studied. Lower mitral annular peak systolic velocity and greater diastolic dysfunction were present in hypertensive patients with ApHCM than in hypertensive patients without ApHCM. Compared with hypertensive patients without ApHCM, hypertensive patients with ApHCM had significantly lower apical longitudinal  and radial strains  without the base-to-apex gradient. The global longitudinal  and circumferential strains  were significantly lower in hypertensive patients with ApHCM than in hypertensive patients without ApHCM. Among systolic parameters, the global longitudinal strain was independently associated with hypertension with ApHCM .Reduced apical longitudinal and radial strains without a base-to-apex gradient were present in hypertensive patients with ApHCM. The global longitudinal strain was independently associated with ApHCM in hypertensive patients. Apical hypertrophic cardiomyopathy (ApHCM), in which the myocardial wall thickening is localized at the apex of the left ventricle, is comparatively rare in western countries in comparison with Asia ,2. ApHCMEchocardiographic strain imaging is an innovative approach recently developed for the assessment of left ventricular myocardial mechanics . MyocardThe study patients were identified through the cardiac care outpatient clinic of Chang Gung Memorial Hospital, Keeling, a tertiary referral hospital. We retrospectively studied the clinical outcomes of consecutive patients with a new diagnosis of hypertension and ApHCM between August 2011 and September 2012. Data were abstracted on demographic characteristics, coronary risk factors, symptoms, and findings on physical examination at the time of presentation, and diagnosis of ApHCM, as well as the most recent follow-up visit. The control group consisted of age-matched asymptomatic patients who had hypertension, but no ApHCM. The study was approved by the Research Ethics Review Board of Chang Gung Memorial Hospital (101-2038B).The echocardiographic inclusion criteria for ApHCM were the following: 1) asymmetric left ventricular hypertrophy confined primarily to the left ventricular apex below the papillary muscle level; 2) apical wall thickness ≥ 15 mm; 3) a ratio of maximal apical to posterior wall thickness ≥ 1.5. Patients were excluded if they had one of following: 1) a severe valvular lesion; 2) sustained atrial or ventricular arrhythmias; 3) prior percutaneous intervention; 4) prior cardiac surgery; 5) prior myocardial infarction; 6) pericardial disease; 7) immunological disease; 8) active infection; 9) moderate to severe anemia or 10) hyper- or hypothyroidism.201thallium myocardial perfusion scan showing reversible/irreversible perfusion defects. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease Study 4-variable equation [Current smoking status was defined as having smoked at least half of a pack of cigarettes per year and having smoked at least one cigarette within 3 weeks before enrollment. Diabetes mellitus was defined as a fasting glucose level ≥ 126 mg/dL or use of hypoglycemic medication. Hypercholesterolemia was defined as a low-density lipoprotein level ≥ 130 mg/dL in a fasting blood sample or use of a statin medication. Hypertension was defined as use of antihypertensive medications or a blood pressure > 140/90 mmHg. Ischemic heart disease was confirmed by 1) coronary angiography, with ≥ 50% diameter stenosis in one or more coronary vessels after administration of intracoronary nitroglycerin or 2) a 2[Electrocardiograms were analyzed for the presence of left ventricular hypertrophy according to the Sokolow-Lyon criteria . The cor2. ‘Giant’m) and the duration of the S-wave (bm) were measured and used to calculate the myocardial performance index as (am-bm)/bm[All echocardiograms were performed by two experienced physicians (M-J and N-I) who used a commercially available system . Images were obtained with patients in the left lateral decubitus position at end-expiration. All standard measurements were obtained in the parasternal long- and short-axis views; apical 4-chamber, 2-chamber, and long-axis views. Two-dimensional and color Doppler imaging were performed to screen for wall motion abnormalities, mitral annulus calcification, and valvular stenosis or regurgitation. For pulsed-tissue Doppler studies, a 2-mm sampling volume was used from the apical 4-chamber view in the septal mitral annulus. The maximal apical wall thickness was obtained as the average of the measurements in the apical 4-chamber and 2-chamber views at end-diastole. Left ventricular ejection fraction and stroke volume were obtained by quantitative 2-dimensional ultrasonography as previously described . Transmiam-bm)/bm. The isoTwo-dimensional strain analysis was performed offline using Echopac software, version 110.1.2  by two independent observers who were unaware of the patients’ conditions. All strain images were obtained at a frame rate of 60–90 frames/s. For each of the three short-axis views, the sampling points were placed manually along the endocardium at the left ventricular base, middle, and apex during end-systole. For each of the 2-, 3- and 4-chamber views, three sampling points were placed manually at the septal mitral annulus, lateral corner, and apical endocardium. A region of interest was then generated by the software covering the myocardial thickness along the entire left ventricular wall. The region of interest was adjusted manually to ensure that the inner margin conformed to the entire left ventricular endocardial border and that it included the entire thickness of the left ventricular myocardium. The software subsequently identified the tissue speckles and tracked their movement frame-by-frame throughout the cardiac cycle.The left ventricular wall was divided into six segments arranged circumferentially at the basal, middle, and apical levels. The software algorithm then calculated longitudinal, circumferential, and radial strains for each segment in graphical form, with automated measurements recorded in tabular form. Peak systolic longitudinal, circumferential, and radial strains for each segment were recorded: the values for all the myocardial segments for each patient were averaged to obtain the global values. End-systole was defined by the time of aortic valve closure and end-diastole was defined by the time of mitral valve closure by Doppler ultrasonography from the apical 4-chamber view.Inter- and intra-observer variability were assessed by two experienced physicians evaluating the raw data of five patients with hypertension and five patients with hypertension and ApHCM in a blinded manner at baseline and at 1 week later. They were instructed to measure strain parameters independently from each other.1-β = 1.00). We performed a sample size calculation using Power Analysis Statistical Software . A sample size of 12 subjects in the control and ApHCM groups would achieve 90% power to detect a difference of 20% strain between the null hypothesis that both group differences in the means are 0.00 and the alternative hypothesis that the differences in means between the two groups is 20% strain, with a 2-sided test and a significance level of 0.05.The sample size calculation was based on the differences in the mean between the two groups with equal sample size, pre-specified 5% type I error, and 90% power , and those not skewed were expressed as means ± standard deviations. For normally distributed continuous variables, a two-sample unpaired t-test was performed. For variables with skewed distributions, the Wilcoxon rank sum test and Fisher’s exact test were used. Receiver-operating characteristic curves were constructed, and areas under curve were calculated. Sensitivities and specificities were determined for the ability to identify ApHCM. Reproducibilities (both interobserver and intra-observer variability) of speckle-tracked echocardiographic parameters were tested using the Bland-Altman statistic. A p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software version 15.0 for Windows .Continuous variables with skewed distributions and Fourteen consecutive patients with hypertension and ApHCM and 14 patients with hypertension without ApHCM were studied. The clinical and electrocardiographic characteristics of the two groups are compared in Table The standard echocardiographic parameters of the two groups are compared in Table Table p < 0.10, i.e., Sm, left ventricular global longitudinal, circumferential, and radial strains. After controlling for these covariates, multivariate analysis showed that global longitudinal strain was an independent predictor of hypertension with ApHCM , circumferential strain , and radial strain  were satisfactory  more left ventricular systolic and diastolic dysfunctions; 2) decreased apical longitudinal and radial strains without a base-to-apex gradient; 3) constantly reduced apical anterior and lateral wall strains irrespective of strain measurement method; 4) independently reduced global longitudinal deformation. Interestingly, these results were obtained from patients with normal left ventricular ejection fractions, highlighting the evidence that alterations of myocardial strain are early contractile abnormalities in hypertensive patients with ApHCM.The outcomes of patients with ApHCM are not as benign as previously thought ,2,5,6. MIn hypertrophic cardiomyopathy patients, longitudinal strain is reduced heterogeneously as assessed by magnetic resonance imaging tagging . SimilarWith characteristic insonation angle independence, 2-dimensional speckle tracking echocardiography allows researchers to investigate cardiac mechanics not only globally, but also regionally; as a result, it is uniquely suited for the assessment of left ventricular apical deformation such as that of ApHCM. In the present study, hypertensive patients without ApHCM (control group) had lower than normal strain values, which is similar to the findings of Mizuguchi et al. . Based oWith the electrocardiographic changes, some investigators found that the late and abrupt development of ApHCM occurs at an elderly age -32. The First, the retrospective design limited data analyses in the present investigation. Second, the number of patients included in the present study was small. Further research with a larger number of patients and a prospective design are needed to confirm our findings. Third, this study was conducted at a single tertiary center study. Therefore, our study population might not represent all patients with hypertension and ApHCM. Nonetheless, there are few if any studies using 2-dimensional speckle-tracking echocardiography for evaluating left ventricular mechanics in hypertensive patients with ApHCM. Therefore, our results provide valuable new insights into understanding the effects of pathological apical hypertrophy on left ventricular function in patients with hypertension. Finally, the incomplete coverage of apical hypertrophy might limit the strain analysis in patients with ApHCM.ApHCM conferred a negative impact on left ventricular function in hypertensive patients. Reduced apical longitudinal and radial strains without a base-to-apex gradient were present in hypertensive patients with ApHCM. These alterations of myocardial strain are evidence of early contractile abnormalities in hypertensive patients with ApHCM. Among the systolic parameters measured, the global longitudinal strain was an independent predictor of hypertension with ApHCM.Written informed consent was obtained from the patient for the publication of this report and any accompanying images.ApHCM: Apical hypertrophic cardiomyopathy; Am: Mitral annular velocity in late diastole; Em: Mitral annular velocity in early diastole; IVRT: Isovolumic relaxation time; Sm: Mitral annular velocity in peak systole.The authors declare that they have no competing interests.Y-C Kao analyzed data and drafted the manuscript M-F Lee, C-T Mao, W-S Chen, N-I Yang and W-J Cherng helped design the study and interpret data; M-J Hung designed the study and interpreted the results. All authors read and approved the final manuscript.


DS-MRI is a well established modality for the diagnostic classification and the risk stratification of patients with coronary artery disease (CAD). However, currently the detection of inducible ischemia by DS-MRI is based on the assessment of cine images, which is subjective and depends on the experience of the readers. In this regard, the human eye primarily tracks the radial displacement of the myocardium with cine-images, which is less sensitive than circumferential and longitudinal components for the detection of myocardial dysfunction.To determine the prognostic value of Strain-Encoded-MRI (SENC) during high-dose dobutamine stress cardiac magnetic resonance imaging (DS-MRI) compared with conventional wall motion analysis.320 consecutive patients with suspected or known CAD underwent DS-MRI, using a standard protocol in a 1.5T MR-scanner. Wall motion and SENC were assessed at baseline and during stress, and outcome data including cardiac deaths, nonfatal myocardial infarctions (‘hard events’) and revascularization procedures performed >90 days after the MR-scans were collected.35 hard events occurred during a 28±9 month follow-up period, including 10 cardiac deaths and 25 nonfatal myocardial infarctions, while 32 patients underwent coronary revascularization. Using multivariable Cox proportional-hazards models, atherogenic risk factors and inducible wall motion abnormalities (WMA) were independently associated with hard events (HR=1.5 (95%CI=1.1-2.1), p=0.02 for the total number risk factors and HR=3.9 (95%CI=1.8-8.6) for inducible WMA, p<0.001, respectively). When inducible strain defects were additionally considered in the model, however inducible WMA were no longer predictive, and SENC yielded the strongest independent association with cardiac outcome (HR of 10.5 (95%CI=2.9-38.5), p<0.001) (Figure Strain-Encoded-MRI aids the accurate identification of patients at high risk for future cardiac events and revascularization procedures, beyond the assessment of conventional atherogenic risk factors and inducible WMA on cine-images.


Recently there has been considerable interest in LV torsion and its relationship with symptomatic and pre-symptomatic disease processes. Torsion gives useful additional information about myocardial tissue performance in both systolic and diastolic function. CMR assessment of LV torsion is simply and efficiently performed. However, there is currently a wide variation in the reporting of torsional motion and the procedures used for its calculation. For example, torsion has been presented as twist (degrees), twist per length (degrees/mm), shear angle (degrees), and shear strain (dimensionless). This paper reviews current clinical applications and shows how torsion can give insights into LV mechanics and the influence of LV geometry and myocyte fiber architecture on cardiac function. Finally, it provides recommendations for CMR measurement protocols, attempts to stimulate standardization of torsion calculation, and suggests areas of useful future research. Left ventricular torsion has long been recognized as a characteristic of normal mammalian cardiac function, described by William Harvey and many others ,2. RelatTorsion has recently gained increasing attention due to two factors. Firstly, simple and direct methods of quantification by non-invasive imaging are now widely available. Initially measured using invasively implanted radiopaque or ultrasonic markers ,10, the Torsion is remarkably consistent across mammalian species, but is affected (either increased or decreased) by a variety of pathologies, including cardiomyopathies , diabeteThis review firstly provides a discussion of how torsion can provide useful additional information on LV mechanical function, followed by an overview of the current clinical applications of LV torsion. It then provides recommendations for standardized protocols for measuring and reporting torsional motion, and finally suggests some useful avenues for future research.CL = 90°- α in Figure in vivo , is faster than the relaxation of axial strains in healthy volunteers . AlthougAnother factor influencing the generation of peak torsion and recoil rate may be the phosphorylation of myosin light chain regulatory proteins ,46. Thertransverse shears, in which cells slide over one another in the radial  direction, have a major contribution to the substantial wall thickening observed during systole [Longitudinal-radial transverse shears have been shown to be mechanically facilitated by myocardial laminae, and maximum local shearing is aligned with the laminae orientation in the subendocardium [circumferential-radial shear). CMR tagging studies have shown that the apical anticlockwise rotation is greater at the endocardium than the epicardium, and the basal clockwise rotation is greater at the endocardium than the epicardium [Although torsion is a shear deformation and therefore volume preserving, it may contribute indirectly to the ejection of blood and the thickening of the ventricular wall during systole. Several studies have noted that  systole   in patients with LV dyssynchrony due to heart failure, LV twist and torsion were negatively correlated with radial dyssynchrony , and these were significantly improved after CRT . Twist aelopment .In pressure overload due to aortic stenosis, relaxation is delayed . The apiIn patients with type 2 diabetes with normal ejection fraction but echocardiographic evidence of diastolic dysfunction, peak systolic torsion was increased relative to controls although peak recoil rate was unchanged . WhetherIn patients with significant iron overload due to repeated transfusions with normal ejection fraction and without heart failure, LV twist was reduced prior to changes in pump function . TorsionTachycardia induced heart failure was associated with decreased and delayed systolic torsion and loss of early diastolic recoil . Dilatedet al [Hansen et al  reportedet al . Transplet al .In patients with ischemic dilated cardiomyopathy who underwent ventricular reconstruction surgery, those patients with the most reduced torsion before reconstruction showed increased torsion afterwards, but over all patients torsion was not significantly increased . Howeveret al.[Torsion may also be a useful biomarker in the study of mechanical effects of genetically manipulated animal models of cardiac disease. In a mouse model of Duchenne muscular dystrophy Li et al. showed iet al.,82.et al. describe a method whereby torsion can be calculated from a single long axis slice using displacement encoded stimulated echo (DENSE) imaging [A variety of CMR imaging protocols can be used to evaluate LV torsion, but currently the relative benefits of each are not known. Torsion can be quantified using velocity encoded tissue phase mapping , spatial imaging . It may  imaging . The mos imaging .An example protocol using standard SPAMM imaging would include short axis cine gradient recalled echo segmented k-space SPAMM tagged acquisition with a flip angle of 5-10° degrees  grid tagging 45° to readout direction with 7 mm spacing, slice thickness 6 mm, repetition time 8 ms, echo time 4 ms, 9 segment view sharing, bandwidth 200 Hz/pixel, giving 23 frames for a 13 sec breath-hold duration. Slices should include at least two short axis locations, one near the apex but including LV cavity at end-systole, and another near the base but including a full circumference of myocardium at end-systole. Reported reproducibility for twist measurements are typically 0.1° for interobserver reproducibility [twist) is not recommended, since this depends on the exact locations of the slices and is difficult to reproduce in longitudinal studies. Twist per unit length of the ventricle is more robust to slice position, since torsion is relatively constant in the longitudinal direction [torsional shear angle shown in Figure There is currently a lack of standardization for methods used to characterize the twisting motion of the left ventricle. For example, torsion has been calculated as relative rotation (degrees) ,65, rotairection , but thiIn solid mechanics, the 3D strain state at any point in a body can be fully represented by three axial strains and three shear strains . ReferreECC is the circumferential axial strain, ELL is the longitudinal axial strain, and ECL is the circumferential-longitudinal shear. Russel et al.[where el et al. have notA two-dimensional approximation of the torsional shear angle can be calculated from the relative rotation of two short axis slices, one basal and one apical in location Figure .et al.[Many studies have used the formula given by Aelen et al. which apet al. [where D is the distance between slices. Intuitively, this approximates the shear angle from the relative circumferential displacement of the base and apex (rϕ), assuming tan(θ)≈θ for small angles. However, this formula assumes that the radii of the apex and base are approximately the same, and can overestimate torsional shear relative to a 3D method . An alteet al.  calculatThis version has been found to give unbiased estimates of the 3D torsional shear angle even in cases with high torsion .Since it has been used in many previous studies, is easy to understand, and relatively invariant to ventricular size and slice position, equation 2 is recommended for the simple calculation of torsion from two short axis slices. However, for direct comparison with the 3D torsional shear, equation 3 is more appropriate. Regional torsion, for example referred to the standard 17 segment model, should not be calculated using either equations 2 or 3, since regional estimates are highly sensitive to the exact position of the axis of rotation . For regFor diastolic function, increased torsion generally leads to increased torsional recoil ,91. For Investigation of the relationship between torsional deformation and the microstructure of the heart, together with the changes due to disease, is likely to be a fruitful area of future research. Detailed information on the myofiber architecture can be obtained from diffusion tensor and diffusion spectrum imaging ,93. AlthOne interesting open question is whether patients with heart failure and normal ejection fraction have impaired relaxation of torsion, since some studies have not found any significant difference . One hypPopulation-based statistical models of cardiac function are now becoming available , in whicA combination of population imaging and mechanical modelling is required to understand the mechanism for the increased torsion found in the subendocardium, and the coupling mechanism which generates transverse shear and wall thickening. In particular, further work is needed on the torsion to shortening ratio to determine if the predictions of computational physiological models of cardiac mechanics  are expeTorsion is an important index of cardiac function and provides additional information on myocardial performance over and above standard pump function indices. Although it is readily performed as part of any CMR examination, standardized methods of calculation are recommended. Torsion provides information on the relative mechanical influence of subendocardial vs subepicardial fibers, and will be particularly useful in characterizing mechanisms through the customization of mathematical models to individual patient torsion.AAY and BRC act as consultants for Siemens Medical Solutions.AAY performed the literature review. Both authors (AAY and BRC) contributed in the design and writing of the manuscript, and approved the final manuscript. JCMR Torsion Movie Base.avi.Click here for file JCMR Torsion Movie Apex.avi.Click here for file


Arterial stiffness had been proposed as the cause of sub-clinical left ventricular dysfunction in patients with COPD. Vascular studies in COPD patients were mainly assessed by carotid-femoral (aortic) pulse wave velocity using micromanometer applanation tonometry. The evaluation of pulmonary artery (PA) elasticity in COPD has not been assessed. This study seeks to evaluate indices of PA stiffness in patients with COPD. We hypothesized that patients with COPD would have increased pulmonary artery stiffness compared to healthy individuals. To test this we determine the pulmonary artery area change (distensibility or pulsatility in %) by cardiac magnetic resonance imaging (MRI) and related PA distensibility to the severity of COPD.100%x(maximum area-minimum area)/minimum area.MRI studies were performed using a 1.5T scanner  on 71 participants recruited to date into an ongoing nested case-control study of current and former smokers, age 58-79 years, free of clinical cardiovascular disease. COPD presence and severity was defined on post-bronchodilator spirometry by GOLD criteria . To measure left ventricular function, the heart was imaged with MRI in short-axis orientation using a retrospectively gated steady-state free precession sequence. Phase-contrast images perpendicular to the pulmonary trunk were obtained using a segmented fast gradient echo sequence  without breath hold. Pulsatility of the pulmonary vessels (in %) was measured from the largest systolic and the smallest diastolic areas derived from the magnitude images as: Participants with COPD had increased PA stiffness compared to normals as shown in Table Patients with COPD may have increased pulmonary artery stiffness measured by MRI PC imaging. Ongoing recruitment into this study is may confirm these preliminary findings.


Natriuretic peptides (NPs) are entered in current guidelines for heart failure (HF) diagnosis and management because of their high specificity and sensibility in screening patients with acute dyspnea. Due to their availability and relatively low cost, they became the first step examinations in HF patients evaluation at hospital admission together with clinical and chest radiography examination. NPs are released following any cardiac haemodynamic stress due to volume or pressure overload and should be considered as a mirror of cardiac condition helping in recognizing patients with poor outcome. Moreover, the exact role of NPs in early HF stages, in isolated diastolic dysfunction, and in general population is questioned. Several promising reports described their potential role; however, the wide cut-off definition, inclusion criteria, and intrinsic measurement biases do not actually consent to their clinical application in these settings. A multimodality strategy including both NPs and imaging studies appears to be the best strategy to define the cardiac dysfunction etiology and its severity as well as to identify patients with higher risk. In this review, we describe the current and potential role of NPs in patients with asymptomatic cardiac insufficiency, evaluating the requirement to obtain a better standardization for imaging as for laboratory criteria. Research regarding the role of serum biomarkers in patients with cardiovascular diseases has grown exponentially over the last ten years. In particular, multiple novel biomarkers have been developed for heart failure (HF), due in part to a well-established pathophysiology, including cardiac dysfunction, neurohormonal activation, and hydrosaline retention –3. At thAlthough the classification of biomarkers helps differentiate each type, this also highlights a potential shortcoming of biomarker development: the fact that they are often studied in isolation, though this trend is recently changing. The ideal laboratory tool fulfills the three criteria outlined by Morrow and de Lemos. Traditionally, three different groups of biomarkers have been identified: (1) laboratory tests, such as natriuretic peptides (NPs) and troponins are defined as “laboratory or molecular biomarkers,” (2) those related to signal, imaging, and functional tests are defined as “functional biomarkers,” and (3) those related to genetic polymorphisms and other genomic tests are defined as “genetic biomarkers.” In this sense, an integrate approach appears mandatory to establish early diagnosis and to optimize the outcome. Moreover, a cardiovascular biomarker can be classified in multiple categories according to its pathophysiological characteristics and/or clinical use. Although this classification is arbitrary, since each index can contain several of these characteristics, it is useful for interpreting the value of an individual clinical biomarker. Regarding laboratory biomarkers, Morrow and de Lemos outlined the three major criteria of a clinically useful biomarker: (1) accurate, reproducible measurements must be rapidly available to the clinician at a reasonable cost; (2) the biomarker must provide additional information beyond careful clinical assessment; (3) knowledge of the measured level should aid in medical decision making . In clinIn the last decade, an “explosion” of data regarding the use of biomarkers in cardiovascular diseases is evident in the literature. This has happened for several reasons: to facilitate diagnosis, improve prognosis both early and late in the course of the disease, and guide management. However, each biomarker has various strengths and weaknesses: some requirements are linked to chemical detection , while others need to respond to clinical requirements  , 7.Laboratory tests are able to identify serial mechanisms potentially involved in the genesis of HF; however, it appears hard to find a single specific biomarker including diagnostic, prognostic, and clinical information all together at the same time. In this context, it appears difficult to identify through laboratory tests the early mechanisms that cause myocardial damage, in order to recognize those subjects at risk to develop the HF syndrome. Frequently, a single biomarker demonstrates exciting results in preliminary studies that cannot be confirmed later in prospective multicenter studies .Early diagnosis of HF depends on the availability of specific, accurate, and effective markers of the disease. For this reason, a multimarker strategy including new and old biomarkers together with traditional diagnostic tools has been recently proposed. Recently, Braunwald classified biomarkers on the basis of each pathophysiologic process that is involved in HF . This clIn the HF setting, patients present with various clinical presentations and in distinct stages of progression; therefore, an ideal biomarker should be able to recognize not only disease severity but also the underlying causal mechanisms and the risk profile . MoreoveMultiple pathophysiologic factors contribute to the development of HF and cardiac impairment. For simplicity, three principal disorders predominate: pump dysfunction, neurohormonal activation, and salt-water retention. However, the clinical presentation resulting from these underlying disorders varies greatly, in part determined by hemodynamic status, primary cardiac disorder, systemic pressure, and organ perfusion/damage , 12. A rHowever, systolic HF is itself a heterogeneous condition with several mechanisms acting as potential contributors: preload, afterload, cardiac contractility and filling, peripheral vascular resistance, and heart rate variability are all important determinants of cardiac performance. The presence of viable myocardium, extension of necrosis, and severity of coronary disease are further determinants of LV function. One of the determinants is the diastolic function that is intimately related to cardiac afterload, and this load dependence is amplified in HF . Acute iThe discovery of NPs as diagnostic biomarkers has been one of the most important advances in the diagnosis of heart failure. Prior to NPs, several studies suggested the need to improve diagnosis, especially with the increasing prevalence of heart failure in the United States . HoweverThe utility of NPs was initially demonstrated in emergency department (ED) patients presenting with acute dyspnea. B-type natriuretic peptide (BNP) levels were a more accurate predictor of HF diagnosis than history, physical exam and routine laboratory tests . The BreNPs measurements appear to be a useful tool for risk stratification; in fact, high levels are associated with recurrent hospitalization and risk of sudden death. Several studies that used natriuretic peptides in predischarge indicate that BNP levels appear to be the strongest predictor for identifying subsequent death or hospital admission within 6 months , 29. In NP measurements are also related to several indexes of systolic and diastolic functions. Traditionally, its samples are linearly increased in relation to the degree of systolic dysfunction and cardiac enlargement , 31. Inv1 ratio. However, NP measurements are not able to differentiate between systolic and diastolic dysfunctions [Some reports have also demonstrated a positive correlation between NP and several markers of LV filling measured traditionally by transmitral Doppler and more recently by tissue Doppler as well as E/Eunctions . A combiunctions . NP showunctions . The preMany studies have demonstrated that there is a reduction in NP after the administration of loop diuretics and other drugs during the acute HF phases. This is due to reduced filling pressure and wall stiffness into LV as well as a decrease in idro-saline retention and in neurohormonal overdrive. In a chronic outpatients group STARS-BNP trial, it was clearly shown that a BNP-guided strategy reduces the incidence of death and rehospitalization for HF . More deFor all the previously cited reasons, NP measurement entered in the last HF guidelines providing additive diagnostic and prognostic information with respect to the previous approach . Such dowries are due to its secretion mechanism: NP, are increased as a consequence of augmented cardiac pressure, volume overload, and wall tension. NP levels are also mediated by means of the renin-angiotensin system and neuroendocrine overdrive; therefore, for specific counterregulatory mechanisms, levels are augmented during idro-saline status retention. Even if NP cannot be considered as “araba fenice,” they should be regarded as the best candidates to provide some additive and complementary information with respect to the traditional tools in the HF setting. HFpEF accounts for around 50% of patients with acute decompensated HF. The diagnosis, at times, may be difficult. Three major conditions need to be recognized: (1) signs and symptom of heart failure, (2) preserved systolic function (EF ≥50 %), and (3) left ventricular diastolic dysfunction  . In clinIn patients with HFpEF, BNP increases according to the degree of diastolic dysfunction: the noninvasive analysis of HF with preserved systolic function is often difficult to establish, LV filling estimation appears particularly complicated in those patients with pseudonormal pattern and E/Ea ratio between 8 and 15. In these patients, BNP can detect diastolic filling pressure helping in the screening and grading its severity . These fAlthough NPs have been emerged as a useful tool in the diagnosis of acute HF and are entered also in the American Guideline algorithms, their significance as a screening device for the general population, namely, to detect asymptomatic patients with LV dysfunction, is currently debated . In the Looking all together at the previously cited data, NPs measurement could appear to be the best solution for few diagnostic and prognostic troubles in clinical practice: measuring NPs, we are able in theory to obtain a variety of information on HF diagnosis, severity, and identification of patients with poor outcome. Unfortunately, several conditions can potentially influence NPs measurements, as demonstrated by Framingham and the Dallas Heart Study data in which a BNP cutoff >80 was able to identify only subjects with severe systolic dysfunction in the general population , 51.Physiologic status race, sex, age, and body mass index are all conditions that could alter NP's synthesis and clearance . RedfielThe most important conditions are comorbidities like renal insufficiency (RI), diabetes, and anemia that are often associated with chronic HF particularly in older patients with more advanced stages . Many stInfluential authors calculated that, in the presence of these associated conditions, NPs values are at least 1/3 higher than those in patients with normal renal function . Anemia  Cut-off limits of NPs have a grey zone in which it is not possible to ascertain their exact diagnostic role, their accuracy, and their predictive values . This raFinally, several cardiac factors can cause NPs alterations even in the absence of increased filling pressure and frank HF: increased LV mass, reduced right ventricular function, mitral valve disease, high pulmonary pressure for primitive or secondary respiratory disease, pulmonary embolism, and atrial fibrillation are all causes of potential NP increase. Overall, these reasons for NP measurement have high sensivity but low specificity, and laboratory test needs to be confirmed by clinical and traditional diagnostic screening processes. NPs are important biomarkers able to assess diagnosis and severity of heart failure as well as predict outcome and potentially guide therapy. Although echocardiography remains the standard regarding detailed information on cardiac performance and structure, imaging data alone is not sufficient to better identify patients with adverse outcome. An integrated approach combining laboratory assays with imaging could lead to a better identification of patients at high risk. This behaviour seems particularly useful in some settings like in patients with isolated diastolic dysfunction as in asymptomatic patients. In patients with diastolic dysfunction, it is sometimes difficult to confirm diagnosis, and NP should help to identify and graduate diastolic dysfunction. In community patients, NPs diagnostic, and prognostic values need to be validated although it is an effective tool to recognize patients with moderate to severe systolic dysfunction. The major limitation consists in the lack of a universally accepted cutoff that could permit the application of NP assays to clinical practice in this setting. The hope is that in the future multimarker strategies together with specificity and cut-off improvements could accurately and early identify patients “under the iceberg” that will develop HF syndrome. In this ideal world biomarkers on one hand and imaging on the other hand could converge to identify patients with higher risk. To obtain this, we need to better standardize echo as well as laboratory parameters.


Cardiac assist devices (CAD) cause endothelial dysfunction with considerable morbidity. Employment of pulsatile CAD remains controversial due to inadequate perfusion curves and costs. Alternatively, we are proposing a new concept of pulsatile CAD based on a fundamental revision of the entire circulatory system in correspondence with the physiopathology and law of physics. It concerns a double lumen disposable tube device that could be adapted to conventional cardiopulmonary bypass (CPB) and/or CAD, for inducing a homogenous, downstream pulsatile perfusion mode with lower energy losses. In this study, the device's prototypes were tested in a simulated conventional pediatric CPB circuit for energy losses and as a left ventricular assist device (LVAD) in ischemic piglets model for endothelial shear stress (ESS) evaluations. In conclusion and according to the study results the pulsatile tube was successfully capable of transforming a conventional CPB and/or CAD steady flow into a pulsatile perfusion mode, with nearly physiologic pulse pressure and lower energy losses. This represents a cost-effective promising method with low mortality and morbidity, especially in fragile cardiac patients. Mechanical cardiac assist devices (CAD) disturb endothelial function and hemodynamics , 2. ThesShear stress-mediated endothelial function controls vascular tone with plenty of mediators , 5 as wedevices that increase coronary blood flow during diastole in order to improve the oxygenation and thus the performance of the myocardium, that is, the intra-aortic balloon pump (IABP) and the enhanced external counterpulsation pump (EECP) [devices that unload and bypass the heart pump either partially as achieved by left ventricular assist devices (LVAD), right ventricular assist devices (RVAD), and extracorporeal membrane oxygenation (ECMO) or completely like with biventricular assist devices, cardiopulmonary bypass (CPB) [In general, present CAD can be identified in two categories: p (EECP) , 9; thesss (CPB) –12.Conceptually, these devices are lumped models, designed for driving Newtonian compressible fluids inside closed pressurized hydraulic circuits implementing rigid tubes with fixed diameters , 14. Mea2), sex (95% men), and age  [Finally, permanent replacement of the heart with an artificial heart option is still a work in progress with short life expectancy, which limits its applications in specific categories, regarding body surface area (1.9 ± 0.22 mhildren) , 17.pharmacological supports [normothermia [pulsatile CPB [In a matter to overrule these side effects, different therapeutic strategies are currently applied, particularly with CPB such as supports , normothothermia , and pultile CPB . Howevertile CPB . Benefittile CPB , remain tile CPB , as the tile CPB . Besidestile CPB . On the tile CPB –28.off-bypass technique, which is still restricted to small groups of patients [These side effects may explain current popularity of conventional CPB , in addipatients .Therefore, an optimum cardiovascular perfusion device is still missing, because we cannot simulate properly a type-III passive ventricular pump with type-I  or type-II  pumps , 32.Alternatively, we are proposing a new concept of pulsatile CAD based on a fundamental revision of the entire circulatory system in correspondence with the physiopathology and law of physics.As shown in , it concIn this study, device prototypes were tested in a simulated conventional pediatric CPB circuit for energy losses and as a LVAD in ischemic piglets model for ESS evaluations.The goals of this study were to evaluate the feasibility of the proposed device to transform a steady-flow of conventional CAD into a pulsatile mode of perfusion with preservation of physiological ESS and minimum energy losses. This represents a cost-effective method with low morbidity and mortality.Device Prototype. A double lumen tube  and positioned at remote spots on the circuit as follows: pre/post-oxygenator ; pre/post-tube , and post-simulated resistance (P5), which represents the arterial perfusion curve in patients  and fixed pulsatile frequency (110 bpm) in group P.Circuit I: the tube was positioned downstream to the oxygenator at 6 cm distance from the aortic cannula.Circuit II: the tube was positioned downstream to the oxygenator at 150 cm distance from the aortic cannula.Circuit III: the tube was positioned upstream between the roller pump and oxygenator.Momentum energy losses were roughly calculated according to differences of flow pressures between the spots (P1–P5) and compared with tube position in 3 different mock circuits as follows.This study was approved by the Animal Research Facility at Sun Yat-sen University and conformed to the Guide for the Care and Use of Laboratory Animals .Ten domestic piglets of both sexes were randomly designated to either pulsatile group  or the nonpulsatile group . Animals were premedicated and maintained on general anesthesia according to our previously published protocols [rotocols . After aCardiac Catheterizations/Hemodynamic Monitoring. A (5 Fr.) double-lumen central venous line  was introduced through the RA purse-string for drug administration and RA pressure monitoring. An intrapulmonary catheter (5 Fr. Swan-Ganz) was introduced through the infundibular purse-string for pulmonary artery pressure (PAP). Left atrium (LA) pressure was obtained by direct needle puncture at predetermined time points. Cardiac output (CO) was measured with a TRANSONIC transit-time flowmeter temporarily positioned around the aortic root at predetermined time points.Total time (T) of the experiment was 3 h, divided into  in correspondence to data collection: T1 = baseline; T2 = nearly 1 h of myocardial ischemia, just before severe hemodynamic deterioration; and T3 = by the end of experiment after 2 h of treatment.Induction of Acute Myocardial Ischemia. After surgical preparation, and data collection for T1, the left anterior descending coronary artery (LAD) was encircled with a 4/0 polypropylene stitch, distal to the 2nd diagonal bifurcation and tightly obstructed with a snugger for 2 h period.During the first 1 h of ischemia, ventricular fibrillation (VF) and cardiac arrest were frequent after 20–30 min of ischemia. Animals were assisted with classical cardiopulmonary resuscitation (CPR) and DC shocks (20–30 J), without any further IHD pharmacological supports.After 30 min, heparin was given (250 UI/kg) intravenously, followed by LVAD installation as follows.In P group, a modified aortic cannula  was inserted at the aortic root and a short piece of PVC tube  was introduced into the LV apex. Both aortic cannula and LV vent were shortly cut in a matter to avoid energy losses caused by unnecessary length. A pulsatile tube prototype was connected at its distal end to a conventional roller pump (Cobe Cardiovascular Inc.) and to the aortic cannula at its proximal end. The LV vent was connected to the other end of the roller pump.In NP group, the aorta was cannulated using a standard aortic cannula  and an apical LV vent . Both aortic and LV vent were connected to a centrifugal pump (Sorin group Revolution).The LVAD circuit in both P and NP groups was primed with heparinized saline, then deaired, clamped, and kept on standby until T2. Animals that did not survive T2 were excluded. Hemodynamics data were collected from both groups at T1, T2, and T3 including AP, PAP, LA, and RA pressures, heart rate, and CO. The vascular resistance index was calculated with the flowing formula:pulmonary vascular resistance index (PVRI) = 80 ∗ (MPAP – PCWP) / CO ∗ Wt,systemic vascular resistance index (SVRI) = 80 ∗ (MAP – CVP) / CO ∗ Wt,where MPAP is the mean pulmonary arterial pressure, PCWP is the pulmonary capillary wedge pressure, substituted for LA pressure, MAP is the mean arterial pressure, CVP is the central venous pressure, substituted for RA pressure, CO is the cardiac output, and Wt is the body weight.Therapeutic Phase. During the second hour of ischemia in P group, the pulsatile tube generator was switched on at a fixed frequency (90 bpm) and irrespective of heart rate (93.755.25 bpm). The flow rate of the roller pump was kept around 0.3 L/min (150 mL/Kg). In the NP group, the centrifugal pump flow rate was fixed around 0.8 L/min.After 1 h of LV mechanical assist, the LAD snugger was released, allowing coronary reperfusion during the second hour of assistance .The ischemic zone was measured and evaluated macroscopically until the end of the experiment (T3).Animals were euthanized with a 10 mL injection of saturated potassium chloride (KCl) upon completion of 3 h of LVAD or just before severe hemodynamic deterioration.Statistics. Continuous variables are expressed as the mean SEM. Comparisons between groups of independent samples were performed with students t-test hemodynamic data in vitro and a 2-way ANOVA for the in vivo data. P with a value less than 0.05 was considered statistically significant. GraphPad Prism software was applied for all the statistical analyses in this study.In vitro, as resumed in P < 0.001).Reduction of the pulsatile perfusion curve amplitude was directly proportional to distance between aortic cannula and tube position; that is, I > II > III.The collected pulse pressure data from each circuit were as follows.≈ 7 mmHg.Circuit I = P4  − P5  ≈ 44 mmHg.Circuit II = P3  − P5  ≈ 26 mmHg. In circuit III, there were significant increased flow pressures in a retrograde manner; that is, P1 > P2 and P5 > P1 (P < 0.001).Circuit III = P2  − P5  In vivo, as resumed in (P < 0.05). Hemodynamic (P > 0.05), respectively. There was significant vasodilatation in the P group compared with NP; mean AP in the P group was 46.830.52 versus 79.881.65 in NP group ; mean PAP in P was 24.832.88 versus 34.537.68 in NP group ; SVRI was 451.7224.01 versus 1309.88 ± 151.93; and PVRI was 210.6616.02 versus 566.9897.98 , respectively.sumed in , apparensumed in . Clearansumed in . In P grodynamic  was betthttp://dx.doi.org/10.1155/2013/651769.For further details please refer to the supplementary attached operative movies available online at In this study, conventional steady-flows of a simulated CPB circuit and LVAD were transformed successfully into a pulsatile mode of perfusion, using a double lumens tube device.In vitro, there were significant pressure losses with tube position in circuits III and II compared with I. In vivo, the induced pulsatile perfusion curve was efficient to improve hemodynamic and restore endothelial function in the P group compared with NP group.Normally, fluid movement in hydraulic circuits, which means momentum transfers with frictional losses, depends on driving forces, resistances, viscosity, and conduits geometries .in vitro remain controversial due to different cardiovascular criteria [Nevertheless, quantifications of lumped models that could be achieved with accuracy according to the Bernoulli's principles of energy losses criteria , 38.Endothelial shear stress (ESS) that control vascular resistances could be influenced by hemorheological changes, particularly, pulse pressure and/or shear rate , 40.For example, under normal hemorheological conditions, microcirculation behavior approaches that of Newton's second law, such as seen in athletics; that is, a high physical performance (ESS) can be induced by increasing the pulse pressure and slowing the heart rate (shear rate). In contrast, in any abnormal hemorheological state, microcirculation presents behavior that approaches that of Bernoulli's 3rd equation, which is interpreted by the Fahraeus-Lindqvist effect , in whicTherefore, delivery of ESS with pulsatile CAD should be induced according to the biophysics and pathophysiological conditions of each heart circuit .Physiologically, the left heart side has specific morphological particularities that must be considered.The left ventricle (LV) and peristaltic arteries represent the main circulatory driving forces at the left heart circuit, which deliver almost constant shear rate and pulse pressure. Flow dynamics inside the valsalva sinuses determines coronary ostia morphogenesis  and may The main target at the left heart side is maintenance organs microcirculation with adequate ESS. And this may explain common phenomena like postoperative or postpartum depression syndrome , 44, by Contrarily to the left heart side, the right heart side can adjust blood volume and shear rates at five different anatomical zones according to its physiological demands . The PA These may explain insufficiency of current CAD employments in congestive heart (CHF) patients with severe RV failure that still exhibit a high mortality rate (65%–95%) . In pedileft heart. This promotes pulsatile tube applications with conventional CPB and LVAD or as biventricular-assist device in association with a pulsatile suit device for a right ventricular-assist device [The proposed pulsatile tube device adapts to biophysics and pathophysiological conditions of the t device .or pre-aortic cannula (Z3), aortic cannula (Z4), and cardiovascular system (Z5).Practically, and for better understanding of the pulsatile tube's function as a cardiovascular perfusion device, we propose a state of momentum energy losses that could be identified in 6 main zones  as folloNormally, pulsatile tube (Z2) receives steady-flow from Z1, then the propagated pulsatile impacts move the stagnant blood boundaries' layers at the inner flexible tube and push them towards the center according to the “Bernoulli” principles. These would promote fewer traumatic effects of blood components compared with current devices. In addition, the downstream position of the pulsatile tube, which avoids already two obstructive zones of energy losses, makes high cost accessories unnecessary , 51The present study results showed the importance of energy losses in correlation to circuits length. Particularly, the distance between the pulsatile tube and the pre-aortic cannula (Z3), was represented by P4 in position (I), P3 and P2 in positions II and III, respectively. Eventually, these constitutions of vortices in Z3 are the consequences of strong pulsatile impacts inside rigid tubes with fixed geometries. Thus, compromising this Z3 distance between patients and CAD is crucial.In contrast, energy losses were very important with tube position in circuit III, which simulates current pulsatile CPB and/or CAD. We have observed severe leakage after few minutes of pulsations (≤5 min) with circuit III. The increased pressure at P5 due to this retrograde turbulent flow was enhanced by the application of a nonocclusive pump . In addiEnergy losses inside the aortic cannula (Z4) are usually caused by unnecessary length and tapering end. We have attempted to diminish these drawbacks of unnecessary length by shortening the aortic cannula in the P group.At the cardiovascular side (Z5), turbulent flow of energy losses that starts from the tip of aortic cannula (divergent diffuser) will be absorbed by the arterial wall filter to be dependent on ESS that control organs microcirculations .According to the present study results, the induced pulsatile tube pulse pressure of the  improvedContrary to the NP group, the induced vasodilatation of the pulsatile group was most probably caused by endothelial vasodilators secretion (e.g. NO), which means maintenance of ESS with tube pulsations. By the end of the experiment (T3), heart rate was 76.255.12 bpm in group P compared with 99.25 ± 3.77 bpm in the group NP, which signifies better hemodynamics with less myocardial oxygen consumption.Interestingly, myocardial recoveries in the pulsatile group occurred in pediatric immature myocardium of animal model with poor coronary collaterals , 54. Thiin vivo studies, the tube pulsations were not synchronized with heart rate. This confirms our therapeutic policy based on similar observations with other pulsatile devices , proving that pulsatile CAD should not be synchronized with the heartbeat in case of heart failure [We should emphasize that in all our  failure .Interestingly, the pulsatile tube was tested as a stimulator of the LV subendocardium without association roller pump, in two ischemic piglets (please refer to the supplementary attached movies). There was rapid clearance of the ischemic zone and improved contractility, after few minutes of unsynchronized pulsations , followed by severe vasodilatation.This proved the hypersensitivity of the LV endocardium and heterogeneity of the left heart endothelium that may be an emerging concept regarding the endothelial impact of current devices , 57.Although these results proved that pulsatile tube was efficient to maintain ESS, some weak points must be improved. This includes microporosity of the inner tube (PTFE), which became almost collapsed by the external latex membrane cover. Accordingly, tube association with a hypersensitive sophisticated centrifugal pump was impossible. There were centrifugal pump failures in two excluded piglets from the NP group due to uncontrolled systemic hypertensive crises (≥140 mmHg). Therefore, the use of a nonocclusive roller pump increased the circuits' artifacts, particularly III and II, and disturbed the applications of more recent formulae for energy losses evaluations , 34. In The proposed study concept deserves further evaluations with more enlarged investigations. To overcome the current limits, we are developing a new device with an inner tube made of ChronoFelx AR, which is similar to PTFE hardness (65 A–75 A) but without micropores. These enabled us to continue our ongoing studies: (a) pulsatile versus nonpulsatile LVAD in ischemic piglet models; (b) biventricular assist device combining the pulsatile tube as a LVAD and the pulsatile trouser as right ventricular assist device (RVAD) . We are Pulsatile tube adaptable to conventional perfusion devices could induce homogenous, downstream, and nearly physiologic pulsatile perfusion flow, with lower energy losses. This represents a cost-effective promising method with low mortality and morbidity, especially in fragile cardiac patients.1st Movie "Pulsatile Tube tested in vitro and in vivo": first part of the movie (in vitro study) shows the pulsatile tube integrated the arterial perfusion line of a mock cardiopulmonary bypass circuit (Circuit I). The middle part of the movie shows the arterial pressure curve obtained by the tube connected as LVAD on an arrested heart. End of the movie shows the tube connected to conventional roller pump as LVAD.2nd Movie: shows a control group piglet assisted with a conventional LVAD using a continuous flow centrifugal pump. The dark infracted zone was present after ≥ 1 h of assistance.3rd Movie: shows the pulsatile tube tested as CAD per se (without to be connected to a perfusion pump). There were macroscopic clearance of the infarcted zone and improvement of myocardial contractility, to be followed by severe vasodilation occurred after 5 minutes of pulsations, most probably due to massive release of endothelial mediators.Click here for additional data file.


We would like to thank the author for their interest in our manuscript  as well  In our case we successfully ablated an arrhythmia focus originating from a normally appearing RV free wall in a patient in whom the transthoracic echocardiogram and cardiac magnetic resonance (CMR) showed features consistent with left ventricular non-compaction cardiomyopathy (LVNC). On the steady state precession cines and late gadolinium enhancement images on the CMR there was no features of RV dilatation, regional wall motion abnormality or reduced systolic function  which are all diagnostic criteria seen in ARVD/C. Moreover, the CMR did not show any features of intra-myocardial fatty infiltration or replacement fibrosis, RV hypertrophy or localized aneurysm formation that is further reported in this cohort of patients . Likewise the 12 lead ECG in our patient showed no repolarization abnormalities that can be seen in ARVD/C. We appreciate that a non-specific or normal appearing ECG does not always preclude ARVD/C diagnosis, however in the study by Te Riele et al.  quoted b Despite the fact that the RV was macroscopically normal, in our LVNC case the RV did have an arrhythmogenic potential. Because of the difficulty in distinguishing normal variants in the highly trabeculated RV from the pathological non-compacted ventricle, the existence of RV non-compaction is disputed by some authors ,6. Wheth


This study sought to investigate changes in magnetic resonance imaging (MRI) ventricular volumes and vascular dimensions before hemi-Fontan (HF) and before total cavopulmonary connection (TCPC) in children with hypoplastic left heart syndrome (HLHS).The systemic right ventricle (RV) in HLHS is subject to significant changes in volume loading throughout the surgical stages of palliation, particularly after the HF.Fifty-eight patients had paired pre-HF and pre-TCPC MRI for assessment of changes of RV volumes, neoaortic flow, and vascular dimensions.2 to 87 ml/m2 and 50 ml/m2 to 36 ml/m2, respectively) with stroke volume remaining constant (49 ml/m2 vs. 51 ml/m2), leading to an increased RV ejection fraction (51% vs. 59%). These findings persisted after excluding the 3 patients who underwent tricuspid valve repair as part of their HF procedure. Indexed RV end-diastolic volume plotted against neoaortic stroke volume demonstrated a Frank-Starling–like curve that shifted upward after HF. The indexed distal left and right cross-sectional pulmonary artery areas were reduced after HF.Comparison of pre-HF and pre-TCPC MRI results showed a decrease of indexed RV end-diastolic volume and end-systolic volume (98 ml/mIn HLHS, serial MRI shows the adaptation of the systemic RV after HF with volume reduction in the context of a preserved stroke volume and an increased ejection fraction. The staged palliation in HLHS may be a risk factor particularly for reduced left pulmonary artery growth in itself as no factors investigated in this study were found to significantly impact on this. Hypoplastic left heart syndrome (HLHS) describes the spectrum of left heart under-development, rendering the left side of the heart unable to support the systemic circulation. Before the 1980s, HLHS was universally fatal, with the majority of children dying within 30 days .Standard investigative management before HF and TCPC has included cardiac catheterization for invasive measurement of pressure and to visualize pulmonary artery anatomy , althougIn this study, we investigate the vascular and ventricular changes that occur after HF with serial MRI scans with central venous pressure measurement from the internal jugular vein.Ethical and institutional approval was obtained (08/H0810/058). Inclusion criteria were all patients with HLHS who had undergone the Norwood procedure, HF, and TCPC from February 2003 to July 2010, and had pre-operative evaluation with cardiac MRI. Patients were identified using the departmental database . The HLHS was defined as any combination of mitral stenosis or atresia with aortic stenosis or atresia  necessitating Norwood palliation .Central venous pressure measurement was performed in all patients pre-TCPC during the same general anesthetic as the MRI. If the central venous pressure was >16 mm Hg, MRI and cardiac catheterization in a hybrid MRI catheter suite was performed, allowing calculation of pulmonary vascular resistance . AdditioAll MRI scans were performed on a Philips 1.5-T Achieva Scanner  under general anesthetic. The coil was selected according to the patient's size. Either a small or medium 2-element flexible coil  was used in neonates and infants, respectively. In patients weighing >15 kg, a standard 5-element cardiac coil (3 anterior and 2 posterior elements) was used. Four-electrode vector electrocardiography was used for cardiac triggering. All patients were examined supine with vector electrocardiographic leads on the anterior hemithorax. After a survey and sensitivity encoded (SENSE) reference scan, a real-time, interactive, steady-state-free precession (SSFP) sequence was used to identify the imaging planes that would be used in subsequent scans.All cine images were electrocardiography triggered and performed with cessation of ventilation for the duration of each acquisition. First, for assessment of the cardiac rest period and the subjective degree of tricuspid regurgitation (TR), a 4-chamber view in high temporal resolution was acquired with a retrospective vector electrocardiography-gated SSFP 2-dimensional cine sequence . Reducing the temporal resolution of this sequence, short-axis cuts for assessment of ventricular function were acquired . The extracardiac vasculature was imaged then, using a first-pass 3-dimensional (3D) angiography technique after intravenous injection of an extravascular contrast agent , 0.1 mmol per kilogram body weight; 200 to 320 mm FOV, 1.2 to 1.7 mm isotropic voxel size, acceleration factor (SENSE acquisition) 2, flip angle 40°, breath-hold time 12 s to 17 s per phase (2 phases acquired).Subsequently, a 3D SSFP whole-heart MR coronary angiography sequence was applied for imaging of the great vessels and cardiac anatomy. Navigator gating  was used to compensate for respiratory motion in our anesthetized patients. For contrast enhancement, a flow-insensitive T2-prepulse for suppression of myocardial signal and a spectrally selective fat saturation pulse were used . Other iThe RV end-diastolic volume (EDV) and end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) were calculated from a stack of short-axis 2-dimensional SSFP cine images using the disc summation method after tracing endocardial contours in end diastole and end systole.Phase contrast flow measurements were analyzed to calculate neoaortic, superior caval vein, and in pre-TCPC patients, branch pulmonary artery flow. Superior caval vein flow was obtained below the innominate and measured bilaterally if the patient had bilateral superior caval veins. Neoaortic flow was measured below the level of the Damus-Kaye-Stansel anastomosis. Differential pulmonary blood flow was calculated from independent branch flows or in some patients with only superior caval vein and 1 branch pulmonary artery flow from right pulmonary artery (RPA) = superior caval vein minus left pulmonary artery (LPA) or LPA = superior caval vein minus RPA. All volumes and flows were indexed to body surface area . DiffereGadolinium-enhanced angiography was preferred for the branch pulmonary artery measurements as the authors found this provided better image quality for small branch pulmonary arteries than 3D SSFP. For larger vessels, both techniques have been shown previously to yield similar results . Branch As the effect on the RV was more likely to be due to the residual morphology of the left ventricle (LV) than the presence/absence of forward flow, LV morphology was described as follows: no LV visible or slitlike LV; globular LV; or borderline LV. Borderline LV was defined as a more mildly hypoplastic LV that could be considered potentially able to support the systemic circulation . In geneTricuspid regurgitation was qualitatively classified as none/trivial/mild or moderate/severe from the 2-dimensional SSFP cine images. If quantitative data were available, tricuspid regurgitant fraction was calculated from ventricular stroke volume (from short-axis stack) less neoaortic forward flow (from phase contrast flow) and expressed as a percentage of the ventricular stroke volume. Patients with large ventricular septal defects were excluded from the quantitative assessment of TR because of the unquantified shunt across the ventricular septal defect.The presence and type of collateral vessels  were recorded on the basis of a review of gadolinium-enhanced angiography and 3D SSFP images assessed using multiplanar reformat. This is a retrospective study, and aortopulmonary collateral flow was not quantified. All analyses (flows and volumes) were performed using Viewforum EWS version 2.0  by 2 members of the research team , blinded to each other's analysis. Observers were blinded to the clinical data.Central venous pressure was measured using a water manometer connected to a cannula in the internal jugular vein. The measurements were converted from centimeters of water to millimeters of mercury. Patients who underwent MRI cardiac catheterization had direct pressure measurements of the branch pulmonary arteries with wedge pressures to calculate the transpulmonary gradient and, combined with MRI phase contrast flow, pulmonary vascular resistance  using tht tests and Wilcoxon signed-rank tests as appropriate. Interuser variability of the right ventricular volume measurements was quantified using an intraclass correlation coefficient 2-way model with absolute agreement , whereby each single measurement was assessed by 2 authors  .Statistical analyses were undertaken using Stata version 11 . Bivariate comparisons comprised paired ., A.B.) . Linear Of note, all model stability and outlier checks outlined above revealed no problems.Between February 2003 and July 2010, 75 patients with HLHS have undergone the Norwood procedure, HF, and TCPC at our institution . Three pDemographics and cardiovascular morphology for the patients are described in There was good agreement between the 2 observers. Intraclass coefficient  was 0.945 (0.741 to 0.91), 0.952 (0.779 to 0.984), 0.926 (0.780 to 0.970), 0.885 (0.764 to 0.946), and 0.999 (0.997 to 0.999) for EDV, ESV, SV, EF, and neoaortic stroke volume, respectively.Bland-Altman comparisons for the stroke volumes derived by the 2 methods (volumetric assessment of the ventricle and phase contrast flow imaging in the neoaorta) agreed closely. Before HF, the mean bias and precision (expressed as a percentage of the averaged stroke volume for each patient) was 1.9 ± 11.9%; before TCPC, the figure was 3.8 ± 8.5%.2 to 4.5 l/min/m2, an 18% fall)  . Indexed2 0.68), with ventricular morphology and degree of TR (assessed subjectively on cine images) pre-HF contributing to the bulk of the remainder. After adjustment for the other variables, the pre-HF indexed volumes contributed on average to a 12% drop in iEDV (coefficient −0.71) and a 24% drop in iESV (coefficient −0.70), meaning that the largest absolute fall was seen in patients with the most dilated ventricles.A linear regression model  was usedPatients with a borderline LV that is still contributing to cardiac output also appeared to have a greater degree of remodeling, with on average an additional 20 ml fall in iEDV after HF. This was seen to a lesser degree in those with a globular LV morphology. There was no significant difference in residual LV volumetry after hemi-Fontan in patients with a borderline LV.Presence of aortopulmonary collaterals pre-HF had a negative impact on remodeling, on average adding 6.2 ml to the iEDV. Age at HF was not associated with a change in iEDV or iESV, nor was the use of angiotensin-converting enzyme inhibitor therapy at the time of the pre-HF scan.The group-averaged relationship between iEDV and indexed neoaortic stroke volume before and after HF (n = 58) is described in 2 went from 0.79 to 0.77), and neither the significance levels nor the partial r2 values for individual variables changed appreciably. Similarly, the relative changes in coefficients were modest, ranging from −10% to +25%. Thus, we can conclude that the influence of tricuspid valve repair did not have a significant influence on ventricular remodeling. However, this finding must be interpreted with caution, because of the small number of patients who underwent tricuspid valve repair (n = 3).To improve statistical power TR was assessed subjectively on 2-dimensional SSFP cine images in the 58 paired MRI examinations as not all MRI examinations provided enough quantitative data for TR calculation. The presence of moderate or severe TR pre-HF contributed on average an increase of 16 ml to the iEDV. Qualitative assessment of TR calculation correlated with quantitative assessment, which was available in 9 patients with moderate (20% to 40%) or severe (>40%) TR . Three of these patients  underwent tricuspid valve repair at HF. To address the potential influence of these 3 patients on ventricular remodeling, we performed a sensitivity analysis by rerunning the regression model seen in Pulmonary artery and aortic dimensions are summarized in We examined whether LPA size at the narrowest point (after adjustment for age) at MR1, MR2, or change in LPA size (after adjustment for age and presence of left pulmonary arterioplasty before MR2) was associated with a range of anatomical and flow-related factors. Anatomical factors included ventricular dilation (iEDV) and proximal aortic area (neoaorta and native aorta). Flow-related factors included total cardiac output (pre-HF only), presence of shunt narrowing (pre-HF only), and collaterals (both aortopulmonary and venovenous). Left pulmonary artery growth was weakly associated positively with proximal aortic area growth; however, no other factor was consistently associated with LPA narrowing.There was no significant difference in the indexed sizes of the native aorta, transverse aortic arch, and proximal descending aorta after HF, even once patients with residual coarctation requiring repair between the pre-HF and pre-TCPC MRI scans are accounted for. The indexed area of the descending aorta at the level of the diaphragm, however, significantly reduces after the HF. However, that was neither correlated with reduced cardiac output  nor with reduced stroke volume .There was no correlation between central venous pressure and any of the measured ventricular or vascular variables with correlation coefficients, ranging from −0.22 to 0.16 .Median follow-up was 766 days . Current life status was checked by using their National Health Service number. There was 1 early mortality (<24 h) from an intractable arrhythmia. No patients required takedown of the TCPC, extracorporeal membrane oxygenation, or transplantation. Three patients have protein-losing enteropathy, and 2 of these patients have required LPA stenting (228 and 320 days after TCPC) to optimize hemodynamics. One patient had a permanent pacemaker implanted for symptomatic bradycardia related to nodal rhythm, and another required cardioversion for 1 episode of atrial flutter.The patient cohort observed in this study showed that serial MRI in HLHS provides comprehensive information on right ventricular function and vascular morphology.An interesting observation is the intermediate-term outcome of those patients assessed with MRI coupled with central venous pressure measurement without cardiac catheterization. Our results are comparable to the published literature . TherefoThe range of right ventricular volumes was wide, encompassing patients with moderate or severe TR and smaller volumes in those with significant forward flow through the left heart. The reduction in volume loading after HF, with iESV and iEDV both falling as expected, led to an increase in EF, although there were no factors that predicted the increase in EF. A reduced fall in ventricular volumes was associated with significant TR as well as the presence of aortopulmonary collaterals, both of which are known to volume load the ventricle. As the majority of patients (84%) in this group had 3.5-mm shunts, it was not possible to evaluate the effect of shunt size.It was noted that nearly all of the patients with moderate or severe TR before HF also had moderate or severe TR before TCPC, and so persistent TR would explain this adverse remodeling and increase in iEDV . This also suggests that the moderate or severe TR is not purely a result of annular dilation, but an inherent abnormality of the tricuspid valve. Interestingly, age at HF was not significantly associated with greater reduction in ventricular volumes and suggests that early surgery does not appear to be indicated solely to help with the post-HF remodeling process.Normal ranges for MRI EF have previously been described in the post-TCPC single ventricle setting , but we There was a marked discrepancy in the relative sizes of the RPA and LPA, with the proximal LPA being approximately two-thirds of the size of the RPA past the HF anastomosis. This discrepancy was more marked before HF. The mechanism of this is likely to be related to the change in the flow dynamics of pulmonary blood flow, for example, from an arterial shunt in the RPA directing more of the flow into this vessel, to the lower pressure HF anastomosis redistributing the blood more evenly. Of note, the superior vena cava iSV positively correlated with the RPA size.Left pulmonary artery stenosis is known to be a significant problem in HLHS . In thisThere was no aortic narrowing in any of the patients pre-TCPC. The 3D MRI images show that the areas reconstructed in the initial Norwood surgery  did not remodel after HF. That is likely to be related to reduced compliance of these vessels secondary to the incorporated homograft tissue. This extends beyond the point where the duct was attached by at least 5 mm into the proximal descending aorta. Conversely, the proximal descending aorta is already larger after surgery than it might be expected in a normal aorta. At the diaphragm, no operation was performed and, therefore, the aorta is growing at a normal pace.2, which is probably due to the reduced cardiac output through the aorta after HF.As there is significant somatic growth between the 2 MRI scans, areas indexed to body surface area were chosen for statistical analysis. Recently, Voges et al.  showed rChanges in indexed neoaortic stroke volumes versus end-diastolic volumes across the whole cohort resembled the Frank-Starling relationship . This cuPulmonary to systemic blood flow ratio was not assessed in the pre-HF patients, and aortopulmonary flow was not quantified. Therefore, the relation of these to RV remodeling could not be evaluated quantitatively. The MRI scans were performed under general anesthetic, which can affect systemic and pulmonary vascular resistances, particularly in the single ventricle setting when the patient is supine with positive pressure ventilation. For assessment of outcome using MRI coupled with central venous pressure, no control group using cardiac catheterization only for pre-operative evaluation was available.Performing MRI scans before HF and TCPC allows an insight into vascular and right ventricular remodeling of the systemic RV. The HF operation appears to not only volume off-load the ventricle (with significant reduction in RV iEDV and iESV) but may also improve contractility. The staged palliation in HLHS may be a risk factor particularly for reduced LPA growth in itself, as no factors investigated in this study were found to have a significant impact on this.


The real-time and continuous assessment of left ventricular (LV) myocardial contractility through an implanted device is a clinically relevant goal. Transvalvular impedance (TVI) is an impedentiometric signal detected in the right cardiac chambers that changes during stroke volume fluctuations in patients. However, the relationship between TVI signals and LV contractility has not been proven. We investigated whether TVI signals predict changes of LV inotropic state during clinically relevant loading and inotropic conditions in swine normal heart.max and LV volumes. Myocardial contractility was assessed with the slope (Ees) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea) and stroke work (SW) were determined from the LV pressure-volume loops. Pigs were studied at rest (baseline), after transient mechanical preload reduction and afterload increase, after 10-min of low dose dobutamine infusion , and esmolol administration .The assessment of RVTVI signals was performed in anesthetized adult healthy anesthetized pigs (n = 6) instrumented for measurement of aortic and LV pressure, dP/dtmax during LDDS and ESMO administration. In addition, the fluctuations of ESTVI were significantly related to changes of the Ees during afterload increase, LDDS and ESMO infusion.We detected a significant relationship between ESTVI and dP/dtESTVI signal detected in right cardiac chamber is significantly affected by acute changes in cardiac mechanical activity and is able to predict acute changes of LV inotropic state in normal heart. The ideal index of ventricular performance, which describes the pumping properties of the left ventricle, should be sensitive to changes of left ventricular (LV) inotropic state, independent of loading conditions, easily reproducible and safe In fact, the continuous real-time assessment of the LV myocardial contractility by an implanted device could provide useful information to calibrate the electrical stimulation in proportion to the real inotropic state of the heart and to monitor maladaptive hemodynamic response to electrical therapy of the heart The signal of intracardiac impedance is a well known parameter for assessing in real time the acute changes of LV performance of failing heart at rest Six healthy sexually mature male farm pigs , fasted overnight, were sedated with a cocktail of tiletamine hydrochloride and zolazepam hydrochloride (8 mg/kg i.m.) andmax and dP/dtmin) and LV volume were measured using a pressure-volume conductance catheter  percutaneously inserted through the femoral artery and carefully advanced into the LV cavity under fluoroscopic guidance premedicated with atropine sulfate (0.1 mg/kg). General anesthesia was subsequently induced with propofol (2–4 mg/kg) and maintained with 1% isoflurane in 60% air and 40% oxygen. Mechanical ventilation was adjusted based on arterial blood gas values max), the maximum derivative of change in pressure fall over time (dP/dtmin). The stroke volume (SV) was calculated as the difference between EDV and ESV. LV DP/dtmax is an index of the isovolumetric phase of the contraction, which is sensitive of preload, but not of afterload The hemodynamic parameters were determined during one respiratory cycle and comprised the heart rate (HR), the mean arterial pressure (MAP), LV end-diastolic (EDV) and end-systolic volume (ESV), LV end-diatsolic (EDP) and end-systolic pressure (ESP), the maximum derivative of change in pressure rise over time . The analogic signals were recorded through an analogic-digital interface , at a sampling rate of 250 Hz AcqKnowledge, Microsoft, USA). The VEGM signal represented the time marker of electrical ventricular activation and the trigger of TVI measurements. TVI increased in systole and decreased in diastole. The minimum and maximum values recorded in 500 ms after VEGM detection were considered, respectively, as the end-diastolic (ED) and ES TVI. The peak-to-peak TVI amplitude (pkpkTVI) was calculated as the difference between ESTVI and EDTVI. The ratio of the maximum TVI increase in 100 ms to the pkpkTVI in each cardiac cycle  represented an index of TVI rate of rise.The atrial and the ventricular pacing leads were connected in parallel with an external dual-chamber stimulator  and with the custom-made TVI recorder. TVI was derived between the atrial ring and ventricular tip electrodes, applying subthreshold current pulses of 40 µA at 4 KHz. The waveform was sampled and stored at 1 KHz, together with the atrial and ventricular electrograms , one surface ECG lead, and one accessory signal (either LVP or LVV) derived as analog output of the PV recording equipment. All tracings were displayed in real-time and then analyzed off-line using commercial software  and following esmolol infusion. Acute reduction of LV preload was induced by transient occlusion of the IVC via inflation of large balloon −1·min−1 ), a cardioselective beta1 receptor blocker Guide for the Care and Use of Laboratory Animals.After a 10-minute washout period, the TVI and hemodynamic parameters were evaluated during transient beta-adrenergic blockade induced by esmolol  was utilized for statistical analysis. Intragroup comparisons were performed using the one way analysis of variance followed by the Bonferroni post-hoc pairwise multiple comparisons.max and LVESP/LVESV were calculated as the ratio between each parameter at baseline and during hemodynamic test. Correlations between groups of values were evaluated calculating the best fit, based on least-squares regression analysis. A good correlation was accepted at R value of ≥0.6. For all the statistical analyses, significance was accepted at P value of <0.05.The changes of ESTVI, LVSV, dP/dtLeft ventricular function during changes in loading conditions. As shown in max, LVdP/dtmin, LVESV, LVEDV were significantly decreased during preload reduction in the presence of unchanged heart rate and reduced LVSV by 37.5±1.86% (p<0.05) compared to baseline (16±1.6 vs 24.5±1.5 ml). The LVESP/LVESV and LVSW were respectively reduced by 10.8±7.1 (p<0.05) and 55±15% (p<0.01) compared to normal loading conditions. Conversely, MAP, LVESP, LVdP/dtmax, LVdP/dtmin and LVESP/LVESV were significantly increased during afterload increase in the presence of reduced LVSV by 54.16±2.8% (p<0.01) compared to baseline (10.5±2 vs 24.5±1.5 ml) (±1.5 ml) . The LV ±1.5 ml) .Left ventricular function during changes in inotropic state. As shown in max, LVdP/dtmin, LVESP/LVESV and LVSW were significantly increased during LDDS in the presence of increased LVSV by 41.6±1.76% (p<0.05) compared to baseline (35±1.8 vs 24±1.5 ml). Similarly, the LVEes was increased by 157±4.5 (p<0.001) compared to baseline. Conversely, the administration of esmolol significantly reduced HR, LVESP, LVdP/dtmax, LVdP/dtmin, LVESP/LVESV and LVSW in the presence of reduced LVSV by 40±2.86% compared to baseline (14±2.4 vs 24±1.5 ml) (p<0.05) ((p<0.05) . The LVEAs shown in The abovementioned TVI values during were reduced compared to baseline following esmolol administration, yet pk-pk TVI was unchanged .max during preload reduction was significant and weak .The direct relationship found between ESTVI and LVEes during inflation of the aortic balloon suggested ESTVI as potential index of LV inotropic state. For this purpose, we performed the abovementioned measurements during selective inotropic conditions.max, SW ad Ees in the presence of marked reduction of LVSV. Surprisingly, we observed a significant reduction of ESTVI and EDTVI in the presence of unchanged pk-pk TVI. In addition, we found a direct and significant correlation between changes of ESTVI and LV dP/dtmax (Low dose dobutamine stimulation induced a marked positive inotropic response characterized by the expected significant increase of LV pressures, stroke work and LVEes. In spite of the clear-cut effects on pressure-related parameters, the LVSV was not significantly increased compared to baseline, probably due to the high cardiac rate and consequent shortening of the total filling time. We observed, in fact, a small reduction of the ESTVI and EDTVI in the presence of unchanged pk-pk TVI compared to baseline condition. However, we observed that ESTVI accurately predicts changes of LV contractility  during pdP/dtmax  or LV EedP/dtmax . On the Our findings are encouraging and suggest that ESTVI has good potential for use in the permanent beat-by-beat surveillance of the LV inotropic state in patients with pacemakers. However, there is still much investigation required before ESTVI is considered a reliable sensor of LV inotropic state in the presence of disarrangement of myofilaments, myocardial dyssynchrony or heart failure.The study was performed in the presence of intrinsic AV conduction. It remains to be established whether the TVI properties reported in this study might be affected by changes in right ventricular pacing.Our experimental data demonstrates that TVI can real-time and accurately detect LV preload modifications. In addition, the changes of ESTVI easily predict acute changes of the LV contractile function of normal swine hearts under different inotropic conditions.